Phenylaminopyrimidine amide autophagy inhibitors and methods of use thereof

ABSTRACT

Described herein are compounds that are inhibitors of autophagy and their use in the treatment of disorders such as cancers.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Ser. No. 62/846,251 filed May10, 2019, U.S. Ser. No. 62/846,258 filed May 10, 2019, U.S. Ser. No.62/911,728 filed Oct. 7, 2019, and U.S. Ser. No. 62/911,730 filed Oct.7, 2019, the contents of each of which are incorporated herein byreference in their entireties.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on May 5, 2020, isnamed DCP-079WO_SL.txt and is 27,196 bytes in size.

BACKGROUND

Autophagy (literally meaning “self eating”) is a process that enablescells to recycle cellular organelles, proteins, stored lipids, glucagon,and other materials for the purpose of generating nutrients underperiods of stress. These cellular contents are recycled by engulfment invesicles called autophagosomes. Autophagosomes subsequently merge withlysosomes that degrade the autophagosomal contents for recycling ofnutrients to the cell. Tumor cells are prone to activate autophagy, asthese cells have a high metabolic demand, experience cellular stress,and frequently are in hypoxic environments with limited blood flow andnutrient supply. Moreover, chemotherapy and targeted therapies have beenshown to induce autophagy as a treatment resistance mechanism, andcombination of autophagy inhibition (by genetic loss of functionmutations in autophagy genes or by pharmacologic means) withchemotherapeutic regimens has been shown to suppress tumor growth andtrigger tumor cell apoptosis to a greater extent than single agentchemotherapy.

Mutant Ras proteins drive approximately 30 percent of all humancancers—including 95 percent of pancreatic cancers and 45 percent ofcolorectal cancers, and treatment of these mutant Ras cancers iscurrently an area of high unmet medical need. Mutant Ras cancers arehighly proliferative and depend on basal levels of autophagy forsurvival, suggesting that inhibition of autophagy in these “autophagyaddicted” cancers is a viable therapeutic approach.

Currently, the most widely used autophagy inhibitors are chloroquine andhydroxychloroquine, which are well-known anti-malarial agents. Theseanti-malarials have been thought to block autophagy by being sequesteredin the lysosomal compartment, raising the pH of these lysomes andthereby inactivating proteases that degrade and recycle nutrients. Theseanti-malarial agents have multiple mechanisms of action beyondinhibiting lysosomes and are known to induce retinopathies in patients.Hence there is a need for more targeted agents which selectively blockautophagy and do not exhibit the toxicities of these anti-malarialagents. ULK1 kinase is the initiating protein of autophagy and is aserine/threonine kinase. The ULK1 kinase complex is activated inresponse to cellular stress including nutrient deprivation and energydepletion. Nutrient deprivation activates ULK kinase activity throughinhibition of mTORC1, and energy depletion activates ULK kinase activitythrough activation by AMP-activated protein kinase AMPK. Importantly,kinase dead mutants of ULK kinase block initiation of canonicalautophagy, suggesting that small molecule inhibitors of ULK kinaseactivity would be able to block autophagy.

Further mechanistic studies have shown that genetic deletion of ULK1inhibits autophagy in cancer cells, relieving FOX3A turn-over andupregulation of the pro-apoptotic protein PUMA. In addition to classicalactivation of canonical autophagy, ULK1 kinase activity has been shownto be required for Bcl-2-L-13 mediated mitophagy (autophagy of damagedmitochondria). ULK1 and ULK2 kinases have also been demonstrated torewire cancer cell glucose metabolism. ULK inhibitors may also findutility in blocking these noncanonical protumoral activities of ULK.

Autophagy is also upregulated in host cells and tissues in cancer.Autophagy in pancreatic tissue stellate cells was demonstrated tosupport tumor growth. Pancreatic stellate cells were shown to supportpancreatic cancer tumor metabolism through autophagic alanine secretion.Inhibition of host tissue autophagy was demonstrated to lead to adepletion in circulating arginine (a required amino acid for tumormetabolism and growth) through liver-mediated increases in arginasesecretion. Activation of ULK1 kinase was also shown to inactivate theSTING pathway in immune cells through inhibitory phosphorylation ofSTING, mediating a negative feedback mechanism for limiting an innateimmune cell response mediated by interferons. Thus, not only isautophagy activated in tumor cells (cancer cell autonomous), but also inother cells in the tumor microenvironment or host tissues (cancer callnonautonomous) to support tumor survival and growth.

Mutant Ras cancers are addicted to autophagy. In pancreatic cancer,mutant Ras signals predominantly through the MAPKAP pathway. Mutant Rasactivates RAF kinases, which in turn activate MEK kinases, which finallyactivate ERK kinases: mutant Ras RAF MEK ERK. Despite mutant Rassignaling through the MAPKAP pathway, inhibitors of this pathway haveprovided no or little clinical benefit in clinical trials when used assingle agents. It has been recently reported that inhibition of theMAPKAP pathway induces autophagy as a compensatory survival mechanism.When MEK inhibitors were combined with the autophagy inhibitorhydroxychloroquine, there was synergistic activity leading to regressionof a number of mutant Ras or mutant BRAF cancers. Similarly, when ERKinhibitors were combined with the autophagy inhibitor hydroxychloroquineor chloroquine, there was synergistic activity leading to inhibition ofmutant Ras pancreatic cancers. It has been demonstrated that geneticdepletion of RAF kinases (CRAF and BRAF) led to synergistic anti-tumoractivity in mutant Ras cancer cell lines when autophagy was alsogenetically depleted. In composite, recent publications highlight thatdual inhibition of the MAPKAP pathway and the autophagy pathway inmutant Ras cancers is a promising treatment regimen for patients withmutant Ras cancers. It has also been demonstrated that other targetedtherapies and chemotherapeutic agents activate tumor autophagy as aresistance mechanism; hence there is rationale for combining suchtargeted therapeutics or chemotherapeutic agents with inhibitors ofautophagy.

Mutations in the gene encoding LRRK2 kinase are causative of Parkinson'sdisease. LRRK2 point mutations are found in both familial (inherited) aswell as sporadic Parkinson's disease patients. The most common mutationof LRRK2 in Parkinson's disease is LRRK2 G2019S. These mutations inLRRK2 are gain-of-function mutations that cause overactivation of LRRK2signaling. Ongoing autophagy is a process that is used by brain neuronalcells to maintain health and homeostasis. Autophagy is a process bywhich cells identify, localize, and destroy aged organelles andstructural elements within cells, and particularly in the case ofproteins known to aggregate in neurons, autophagy eliminates such toxicprotein aggregates to maintain neuronal health. LRRK2 activitysuppresses autophagy, and the LRRK2 G2019S gain-of-function mutant evenmore so suppresses autophagy and has been linked to aggressive forms ofParkinson's disease.

Increased LRRK2 kinase activity has also been linked toimmunoinflammatory diseases including colitis and Crohn's disease andinflammatory bowel disease. In the gastrointestinal tract, LRRK2 ispresent in antigen-presenting cells including dendritic cells. LRRK2activity has been shown to be important in Dectin-1 mediated innateimmune responses, including an activation of the NFkB pathway andincreased TNF-alpha production in dendritic cells of patients withCrohn's disease.

Inhibitors of LRRK2 are sought for the treatment of neurodegenerativediseases including Parkinson's disease, and also are sought for thetreatment of gastrointestinal diseases including Crohn's disease,ulcerative colitis, and inflammatory bowel disease.

There is a need for new targeted therapies which inhibit autophagy andcan be used in combination with MAPKAP pathway inhibitors,chemotherapeutic agents, and/or other targeted therapeutics.

SUMMARY

Described herein are compounds that are inhibitors of autophagy,pharmaceutical compositions, and their use as agents in the treatment ofdisorders such as cancer, processes for their preparation, andpharmaceutical compositions containing them as an active ingredient.Such pharmaceutical compositions may comprise the compound as the soleactive agent or in combination with other active agents in the presenceof a pharmaceutically acceptable excipient. In an embodiment, thedescribed compounds are inhibitors of ULK kinase activity, includingULK1 and ULK2 activity.

For example, compounds provided herein may be described as representedby Formula (I)

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, ortautomer thereof, wherein: W is CH or N; X is CH or N; Y is C(R³) or N;R¹ is selected from the group consisting of halogen, cyano, C₁-C₅alkyl,and C₃-C₅cycloalkyl, wherein each C₁-C₅alkyl and C₃-C₅cycloalkyl may beoptionally substituted by one, two or three independent occurrences offluorine; R² is selected from the group consisting of H, halogen, cyano,C₁-C₅alkyl, C₃-C₆cycloalkyl, C₂-C₅alkenyl, C₂-C₅alkynyl, C₁-C₅alkoxy,and C₁-C₅alkoxy-C₂-C₅alkyl, wherein each C₁-C₅alkyl, C₃-C₆cycloalkyl,C₂-C₅alkenyl, C₂-C₅alkynyl, and C₁-C₅alkoxy may be optionallysubstituted by one, two, or three independent occurrences of fluorine orcyano; each occurrence of R³ and R³³ is independently selected from thegroup consisting of H, halogen, C₁-C₆alkyl, and C₁-C₆alkoxy, whereineach C₁-C₆alkyl and C₁-C₆alkoxy may be optionally substituted by one ormore independent occurrences of fluorine; R⁴ is selected from the groupconsisting of B, D, NR⁶R⁹, NR⁶—C(R¹⁰)₂)_(p)—NR⁹R⁹, C(O)—NR⁶R⁹; C(O)—B;C(O)-D, and CN; B is selected from an N-linked heterocyclyl having atleast one nitrogen and optionally having an additional ring nitrogen oroxygen and heteroaryl, wherein B may be optionally substituted on one ormore available carbons by R⁷ and may be optionally substituted on anavailable nitrogen by R⁹; D is selected from a C-linked heterocyclylhaving at least one nitrogen and optionally having an additional ringnitrogen or oxygen and heteroaryl, wherein D may be optionallysubstituted on one or more available carbons by R⁷ and may be optionallysubstituted on an available nitrogen by R⁹; each occurrence of R⁵ isindependently selected from the group consisting of H, C₁-C₆alkyl,C₃-C₆cycloalkyl, and heterocyclyl, wherein each C₁-C₆alkyl andC₃-C₆cycloalkyl may be optionally substituted by one or more independentoccurrences of fluorine; each occurrence of R⁷ is independently selectedfrom the group consisting of H, C₁-C₆alkyl, C₃-C₆cycloalkyl, cyano, and)(C(R¹⁰)₂)_(h)—NR⁹R⁹ wherein each C₁-C₆alkyl and C₃-C₆cycloalkyl may beoptionally substituted by one or more independent occurrences offluorine, or two R⁷ are joined together with the atom to which they areattached to form oxo; each occurrence of R⁶ and R⁹ is independentlyselected from the group consisting of H, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₅alkoxy-C₂-C₅alkyl, C(═O)R⁵, SO₂R⁵, and D, wherein each C₁-C₆alkyland C₃-C₆cycloalkyl may be optionally substituted by one or moreindependent occurrences of fluorine; each occurrence of R¹⁰ isindependently selected from the group consisting of H, C₁-C₃alkyl, andC₃-C₅cycloalkyl, wherein each C₁-C₃alkyl and C₃-C₅cycloalkyl may beoptionally substituted by one or more independent occurrences offluorine, or two R¹⁰ are joined together with the carbon to which theyare attached to form a C₃-C₅cycloalkyl; Z is selected from the groupconsisting of a 4 membered lactam ring bound through the nitrogen atomor a 6-10 membered lactam ring bound through the nitrogen atom, whereina lactam ring atom may optionally be oxygen or NR⁶ when the lactam ringis a 6-10 membered ring and an available carbon atom on 4 memberedlactam ring or a 6-10 membered lactam is optionally substituted by R³⁶;each occurrence of R³⁶ is independently selected from C₁-C₆alkyl andC₃-C₆cycloalkyl, wherein each C₁-C₆alkyl and C₃-C₆cycloalkyl may beoptionally substituted by one or more independent occurrences offluorine, or two R³⁶ are joined together with the carbon to which theyare attached to form a C₃-C₆cycloalkyl; h is 1, 2, or 3; m is 0, 1, 2,or 3; n is 2, 3, or 4; and p is 2 or 3; provided that both X and Y arenot N.

DETAILED DESCRIPTION

The features and other details of the disclosure will now be moreparticularly described. Certain terms employed in the specification,examples and appended claims are collected here. These definitionsshould be read in light of the remainder of the disclosure and asunderstood by a person of skill in the art. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by a person of ordinary skill in the art.

Definitions

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon. Exemplary alkyl groups include, but are notlimited to, straight or branched hydrocarbons of 1-6, 1-5, 1-4, 1-3, or1-2 carbon atoms, referred to herein as C₁-C₆alkyl, C₁-C₅alkyl,C₁-C₄alkyl, C₁-C₃alkyl, and C₁-C₂alkyl, respectively. Exemplary alkylgroups include, but are not limited to, methyl, ethyl, propyl,isopropyl, 2-methyl-1-butyl, 3-methyl-2-butyl, 2-methyl-1-pentyl,3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl,3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl,3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl,isopentyl, neopentyl, hexyl, etc.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond.Exemplary alkenyl groups include, but are not limited to, a straight orbranched group of 2-6 or 3-4 carbon atoms, referred to herein asC₂-C₆alkenyl, and C₃-C₄alkenyl, respectively. Exemplary alkenyl groupsinclude, but are not limited to, vinyl, allyl, butenyl, pentenyl, etc.

The term “alkoxy” as used herein refers to a straight or branched alkylgroup attached to oxygen (alkyl-O—). Exemplary alkoxy groups include,but are not limited to, alkoxy groups of 1-6 or 2-6 carbon atoms,referred to herein as C₁-C₆alkoxy, and C₂-C₆alkoxy, respectively.Exemplary alkoxy groups include, but are not limited to methoxy, ethoxy,isopropoxy, etc.

The term “alkoxyalkyl” as used herein refers to a straight or branchedalkyl group attached to oxygen, attached to a second straight orbranched alkyl group (alkyl-O-alkyl-). Exemplary alkoxyalkyl groupsinclude, but are not limited to, alkoxyalkyl groups in which each of thealkyl groups independently contains 1-6 carbon atoms, referred to hereinas C₁-C₆alkoxy-C₁-C₆alkyl. Exemplary alkoxyalkyl groups include, but arenot limited to methoxymethyl, 2-methoxyethyl, 1-methoxyethyl,2-methoxypropyl, ethoxymethyl, 2-isopropoxyethyl etc.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond.Exemplary alkynyl groups include, but are not limited to, straight orbranched groups of 2-6, or 3-6 carbon atoms, referred to herein asC₂-C₆alkynyl, and C₃-C₆alkynyl, respectively. Exemplary alkynyl groupsinclude, but are not limited to, ethynyl, propynyl, butynyl, pentynyl,hexynyl, methylpropynyl, etc.

The term “cyano” as used herein refers to the radical —CN.

The terms “cycloalkyl” or a “carbocyclic group” as used herein refers toa saturated or partially unsaturated hydrocarbon group of, for example,3-6, or 4-6 carbons, referred to herein as C₃-C₆cycloalkyl orC₄-C₆cycloalkyl, respectively. Exemplary cycloalkyl groups include, butare not limited to, cyclohexyl, cyclopentyl, cyclopentenyl, cyclobutylor cyclopropyl.

The term “cycloalkoxy” as used herein refers to a cycloalkyl groupattached to oxygen (cycloalkyl-O—). Exemplary cycloalkoxy groupsinclude, but are not limited to, cycloalkoxy groups of 3-6 carbon atoms,referred to herein as C₃-C₆cycloalkoxy groups. Exemplary cycloalkoxygroups include, but are not limited to, cyclopropoxy, cyclobutoxy,cyclopentoxy, cyclohexyloxy, etc.

The terms “halo” or “halogen” as used herein refer to F, Cl, Br, or I.

The term “heteroaryl” as used herein refers to a monocyclic aromatic 5or 6 membered ring system containing one or more heteroatoms, forexample one to three heteroatoms, such as nitrogen, oxygen, and sulfur.Where possible, said heteroaryl ring may be linked to the adjacentradical though carbon or nitrogen. Examples of heteroaryl rings includebut are not limited to furan, thiophene, pyrrole, thiazole, oxazole,isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine orpyrimidine etc.

The terms “heterocyclyl” or “heterocyclic group” are art-recognized andrefer to saturated or partially unsaturated, 4-10 membered ringstructures, including monocyclic, bridged or fused rings, and whose ringstructures include one to three heteroatoms, such as nitrogen, oxygen,and sulfur. Where possible, heterocyclyl rings may be linked to theadjacent radical through carbon or nitrogen. Examples of heterocyclylgroups include, but are not limited to, pyrrolidine, piperidine,morpholine, thiomorpholine, piperazine, oxetane, azetidine,tetrahydrofuran or dihydrofuran etc.

As used herein, the term “lactam” refers to cyclic amides of aminocarboxylic acids, having a 1-azacycloalkan-2-one structure, or analogueshaving unsaturation or heteroatoms replacing one or more carbon atoms ofthe ring. An “alpha-lactam,” refers to a lactam comprised of a3-membered ring. A “beta-lactam,” refers to a lactam comprised of a4-membered ring. A “gamma-lactam,” refers to a lactam comprised of a5-membered ring. A “delta-lactam,” refers to a lactam comprised of a6-membered ring. An “epsilon-lactam,” refers to a lactam comprised of a7-membered ring.

The term “oxo” as used herein refers to the radical ═O.

A “combination therapy” is a treatment that includes the administrationof two or more therapeutic agents, e.g., a compound of Formula I and aMAPKAP pathway inhibitor, to a patient in need thereof.

“Disease,” “disorder,” and “condition” are used interchangeably herein.

“Individual,” “patient,” or “subject” are used interchangeably andinclude any animal, including mammals, preferably mice, rats, otherrodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates,and most preferably humans. The compounds described herein can beadministered to a mammal, such as a human, but can also be administeredto other mammals such as an animal in need of veterinary treatment,e.g., domestic animals (e.g., dogs, cats, and the like), farm animals(e.g., cows, sheep, pigs, horses, and the like) and laboratory animals(e.g., rats, mice, guinea pigs, and the like).

A “MAPKAP pathway inhibitor” is an inhibitor of the MAP kinase signalingpathway. Inhibitors of this pathway include Ras inhibitors (e.g.AMG-510, MRTX 849), RAF inhibitors (e.g. dabrafenib, vemurafenib,LY3009120), MEK inhibitors (e.g. trametinib, binimetinib, selumetinib,cobimetinib), and ERK inhibitors (e.g. ulixertinib, SCH772984,LY3214996). The terms “MAPKAP pathway inhibitor” and “MAPKAP kinaseinhibitor are used interchangeably herein.

“Pharmaceutically or pharmacologically acceptable” include molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to an animal, or a human, asappropriate. For human administration, preparations should meetsterility, pyrogenicity, and general safety and purity standards asrequired by FDA Office of Biologics standards.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” as used herein refers to any and all solvents,dispersion media, coatings, isotonic and absorption delaying agents, andthe like, that are compatible with pharmaceutical administration. Theuse of such media and agents for pharmaceutically active substances iswell known in the art. The compositions may also contain other activecompounds providing supplemental, additional, or enhanced therapeuticfunctions.

The term “pharmaceutical composition” as used herein refers to acomposition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

The term “pharmaceutically acceptable salt(s)” as used herein refers tosalts of acidic or basic groups that may be present in compounds used inthe compositions. Compounds included in the present compositions thatare basic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including, but notlimited to, malate, oxalate, chloride, bromide, iodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.Compounds included in the present compositions that are acidic in natureare capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include alkali metal oralkaline earth metal salts, particularly calcium, magnesium, sodium,lithium, zinc, potassium, and iron salts. Compounds included in thepresent compositions that include a basic or acidic moiety may also formpharmaceutically acceptable salts with various amino acids. Thecompounds of the disclosure may contain both acidic and basic groups;for example, one amino and one carboxylic acid group. In such a case,the compound can exist as an acid addition salt, a zwitterion, or a basesalt.

The compounds of the disclosure may contain one or more chiral centersand, therefore, exist as stereoisomers. The term “stereoisomers” whenused herein consist of all enantiomers or diastereomers. These compoundsmay be designated by the symbols “(+),” “(−),” “R” or “S,” depending onthe configuration of substituents around the stereogenic carbon atom,but the skilled artisan will recognize that a structure may denote achiral center implicitly. The presently described compounds encompassesvarious stereoisomers of these compounds and mixtures thereof. Mixturesof enantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly.

In the present specification, the term “therapeutically effectiveamount” means the amount of the subject compound that will elicit thebiological or medical response of a tissue, system or animal, (e.g.mammal or human) that is being sought by the researcher, veterinarian,medical doctor or other clinician. The compounds described herein areadministered in therapeutically effective amounts to treat a disorder.

“Treating” includes any effect, e.g., lessening, reducing, modulating,or eliminating, that results in the improvement of the condition,disease, disorder and the like.

The disclosure also embraces isotopically labeled compounds which areidentical to those recited herein, except that one or more atoms arereplaced by an atom having an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O,³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. For example, a compound ofthe disclosure may have one or more H atom replaced with deuterium.

Individual enantiomers and diasteriomers of compounds of the presentinvention can be prepared synthetically from commercially availablestarting materials that contain asymmetric or stereogenic centers, or bypreparation of racemic mixtures followed by resolution methods wellknown to those of ordinary skill in the art. These methods of resolutionare exemplified by (1) attachment of a mixture of enantiomers to achiral auxiliary, separation of the resulting mixture of diastereomersby recrystallization or chromatography and liberation of the opticallypure product from the auxiliary, (2) salt formation employing anoptically active resolving agent, (3) direct separation of the mixtureof optical enantiomers on chiral liquid chromatographic columns or (4)kinetic resolution using stereoselective chemical or enzymatic reagents.Racemic mixtures can also be resolved into their component enantiomersby well-known methods, such as chiral-phase liquid chromatography orcrystallizing the compound in a chiral solvent. Stereoselectivesyntheses, a chemical or enzymatic reaction in which a single reactantforms an unequal mixture of stereoisomers during the creation of a newstereocenter or during the transformation of a pre-existing one, arewell known in the art. Stereoselective syntheses encompass both enantio-and diastereoselective transformations, and may involve the use ofchiral auxiliaries. For examples, see Carreira and Kvaerno, Classics inStereoselective Synthesis, Wiley-VCH: Weinheim, 2009.

Compounds

Described herein is a compound represented by Formula I:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, ortautomer thereof, wherein: W is CH or N; X is CH or N; Y is C(R³) or N;R¹ is selected from the group consisting of halogen, cyano, C₁-C₅alkyl,and C₃-C₅cycloalkyl, wherein each C₁-C₅alkyl and C₃-C₅cycloalkyl may beoptionally substituted by one, two or three independent occurrences offluorine; R² is selected from the group consisting of H, halogen, cyano,C₁-C₅alkyl, C₃-C₆cycloalkyl, C₂-C₅alkenyl, C₂-C₅alkynyl, C₁-C₅alkoxy,and C₁-C₅alkoxy-C₂-C₅alkyl, wherein each C₁-C₅alkyl, C₃-C₆cycloalkyl,C₂-C₅alkenyl, C₂-C₅alkynyl, and C₁-C₅alkoxy may be optionallysubstituted by one, two, or three independent occurrences of fluorine orcyano; each occurrence of R³ and R³³ is independently selected from thegroup consisting of H, halogen, C₁-C₆alkyl, and C₁-C₆alkoxy, whereineach C₁-C₆alkyl and C₁-C₆alkoxy may be optionally substituted by one ormore independent occurrences of fluorine; R⁴ is selected from the groupconsisting of B, D, NR⁶R⁹, NR⁶—(C(R¹⁰)₂)_(p)—NR⁹R⁹, C(O)—NR⁶R⁹; C(O)—B;C(O)-D, and CN; B is selected from an N-linked heterocyclyl having atleast one nitrogen and optionally having an additional ring nitrogen oroxygen and heteroaryl, wherein B may be optionally substituted on one ormore available carbons by R⁷ and may be optionally substituted on anavailable nitrogen by R⁹; D is selected from a C-linked heterocyclylhaving at least one nitrogen and optionally having an additional ringnitrogen or oxygen and heteroaryl, wherein D may be optionallysubstituted on one or more available carbons by R⁷ and may be optionallysubstituted on an available nitrogen by R⁹; each occurrence of R⁵ isindependently selected from the group consisting of H, C₁-C₆alkyl,C₃-C₆cycloalkyl, and heterocyclyl, wherein each C₁-C₆alkyl andC₃-C₆cycloalkyl may be optionally substituted by one or more independentoccurrences of fluorine; each occurrence of R⁷ is independently selectedfrom the group consisting of H, C₁-C₆alkyl, C₃-C₆cycloalkyl, cyano, and)(C(R¹⁰)₂)_(h)—NR⁹R⁹, wherein each C₁-C₆alkyl and C₃-C₆cycloalkyl may beoptionally substituted by one or more independent occurrences offluorine, or two R⁷ are joined together with the atom to which they areattached to form oxo; each occurrence of R⁶ and R⁹ is independentlyselected from the group consisting of H, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₅alkoxy-C₂-C₅alkyl, C(═O)R⁵, SO₂R⁵, and D, wherein each C₁-C₆alkyland C₃-C₆cycloalkyl may be optionally substituted by one or moreindependent occurrences of fluorine; each occurrence of R¹⁰ isindependently selected from the group consisting of H, C₁-C₃alkyl, andC₃-C₅cycloalkyl, wherein each C₁-C₃alkyl and C₃-C₅cycloalkyl may beoptionally substituted by one or more independent occurrences offluorine, or two R¹⁰ are joined together with the carbon to which theyare attached to form a C₃-C₅cycloalkyl; Z is selected from the groupconsisting of a 4 membered lactam ring bound through the nitrogen atomor a 6-10 membered lactam ring bound through the nitrogen atom, whereina lactam ring atom may optionally be oxygen or NR⁶ when the lactam ringis a 6-10 membered ring and an available carbon atom on 4 memberedlactam ring or a 6-10 membered lactam is optionally substituted by R³⁶;each occurrence of R³⁶ is independently selected from C₁-C₆alkyl andC₃-C₆cycloalkyl, wherein each C₁-C₆alkyl and C₃-C₆cycloalkyl may beoptionally substituted by one or more independent occurrences offluorine, or two R³⁶ are joined together with the carbon to which theyare attached to form a C₃-C₆cycloalkyl; h is 1, 2, or 3; m is 0, 1, 2,or 3; n is 2, 3, or 4; and p is 2 or 3; provided that both X and Y arenot N.

In some embodiments, W is N. In some embodiments, X is CH and Y is N. Insome embodiments, X is CH and Y is C(R³).

In some embodiments, Z is selected from:

wherein V is selected from the group consisting of oxygen, CH₂, and NR⁶;each occurrence of R³⁴ is independently selected from H and R³⁶, whereineach occurrence of R³⁶ is independently selected from C₁-C₆alkyl andC₃-C₆cycloalkyl, or two R³⁶ are joined together with the carbon to whichthey are attached to form a C₃-C₆cycloalkyl; q is 0, 1, 2, or 3; and ris 2 or 4, provided that, if q is 0, then r is not 2.

In some embodiments, Z is selected from:

wherein V is selected from the group consisting of oxygen, C(R³⁴)₂, andNR⁶; each occurrence of R³⁴ is independently selected from H and R³⁶,wherein each occurrence of R³⁶ is independently selected from C₁-C₆alkyland C₃-C₆cycloalkyl, or two R³⁶ are joined together with the carbon towhich they are attached to form a C₃-C₆cycloalkyl; q is 0, 1, 2, or 3;and r is 2 or 3, provided that, if q is 0, then r is not 2.

In some embodiments, Z is selected from the group consisting of:

In some embodiments, Z is selected from:

wherein V is selected from the group consisting of oxygen, CH₂, and NR⁶;q is 0, 1, 2, or 3; and r is 2 or 3, provided that, if q is 0, then r isnot 2.

In some embodiments, Z is selected from the group consisting of:

In some embodiments, R⁴ is B.

In some embodiments, R⁴ is selected from the group consisting of:

wherein u is 1 or 2.

In some embodiments, R⁴ is selected from the group consisting of:

In some embodiments, R⁴ is selected from the group consisting of:

In some embodiments, R⁴ is selected from the group consisting of:

In some embodiments, R⁴ is D.

In some embodiments, R⁴ is selected from the group consisting of:

In some embodiments, m is 0. In some embodiments, m is 1. In someembodiments, m is 2. In some embodiments, m is 3.

In some embodiments, R¹ is selected from the group consisting ofhalogen, C₁-C₅alkyl, and C₃-C₅cycloalkyl, wherein C₁-C₅alkyl may beoptionally substituted with one, two, or three occurrences of fluorine.In some embodiments, R¹ is CF₃. In some embodiments, R¹ is CF₂H. In someembodiments, R¹ is halogen. In some embodiments, R¹ is bromo. In someembodiments, R¹ is cyclopropyl.

In some embodiments, R² is selected from the group consisting of H,C₃-C₅cycloalkyl, C₁-C₅alkyl, halogen, CN, C₂-C₅alkenyl, and C₂-C₅alknyl,wherein C₁-C₅alkyl may be optionally substituted with one, two, or threeindependent occurrences of fluorine. In some embodiments, R² is selectedfrom the group consisting of C₁₋₂alkyl and C₃₋₄cycloalkyl. In someembodiments, R² is selected from the group consisting of chloro andbromo.

In some embodiments, R² is selected from the group consisting ofC₁-C₅alkyl, H, and C₃-C₄cycloalkyl. In some embodiments, R² is selectedfrom the group consisting of C₁-C₂alkyl and C₃-C₄cycloalkyl. In someembodiments, R² is selected from the group consisting of chloro andbromo.

In some embodiments, n is 3.

In some embodiments, the compound is represented by Formula II:

or a pharmaceutically acceptable salt thereof, wherein: n is 2, 3, or 4;R¹ is selected from the group consisting of halogen, cyano, C₁-C₅alkyl,and C₃-C₅cycloalkyl, wherein each C₁-C₅alkyl and C₃-C₅cycloalkyl may beoptionally substituted by one, two or three independent occurrences offluorine; R² is selected from the group consisting of halogen,C₁-C₂alkyl and C₃-C₄cycloalkyl; R⁴ is selected from the group consistingof:

each occurrence of R⁶ and R⁹ is independently selected from the groupconsisting of H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C(═O)R⁵, SO₂R⁵, and D,wherein each C₁-C₆alkyl and C₃-C₆cycloalkyl may be optionallysubstituted by one or more independent occurrences of fluorine; eachoccurrence of R⁵ is independently selected from the group consisting ofH, C₁-C₆alkyl, C₃-C₆cycloalkyl, and heterocyclyl, wherein eachC₁-C₆alkyl and C₃-C₆cycloalkyl may be optionally substituted by one ormore independent occurrences of fluorine; each occurrence of R⁷ isindependently selected from the group consisting of H, C₁-C₆ alkyl, andC₃-C₆cycloalkyl, wherein each C₁-C₆alkyl and C₃-C₆cycloalkyl may beoptionally substituted by one or more independent occurrences offluorine, or two R⁷ are joined together with the atom to which they areattached to form oxo; D is selected from a C-linked heterocyclyl havingat least one nitrogen and optionally having an additional ring nitrogenor oxygen and heteroaryl, wherein D may be optionally substituted on oneor more available carbons by R⁷ and may be optionally substituted on anavailable nitrogen by R⁹; Z is selected from the group consisting of:

and each occurrence of R³⁴ is independently selected from H and R³⁶,wherein each occurrence of R³⁶ is independently selected from C₁-C₆alkyland C₃-C₆cycloalkyl, wherein each C₁-C₅alkyl and C₃-C₆cycloalkyl may beoptionally substituted by one or more independent occurrences offluorine, or two R³⁶ are joined together with the carbon to which theyare attached to form a C₃-C₆cycloalkyl.

In some embodiments, R¹ is selected from the group consisting ofhalogen, C₁-C₅alkyl, and C₃-C₅cycloalkyl, wherein C₁-C₅alkyl may beoptionally substituted with one, two, or three occurrences of fluorine,and C₃-C₅cycloalkyl. In some embodiments, R¹ is CF₃. In someembodiments, R¹ is CF₂H. In some embodiments, R¹ is halogen. In someembodiments, R¹ is bromo. In some embodiments, R¹ is cyclopropyl.

In some embodiments, R² is selected from the group consisting of H,C₃-C₄cycloalkyl, C₁-C₅alkyl, and halogen. In some embodiments, R² isselected from the group consisting of C₁-C₂alkyl, C₃-C₄cycloalkyl,bromo, and chloro.

In some embodiments, R⁴ is selected from the group consisting of:

In some embodiments, R⁴ is selected from the group consisting of:

In some embodiments, each R⁶ and R⁹ is independently selected from thegroup consisting of H, C₁-C₆alkyl, and C₃-C₆cycloalkyl, wherein each ofC₁-C₆alkyl and C₃-C₆cycloalkyl is optionally substituted by one or moreindependent occurrences of fluorine.

In some embodiments, R⁷ is H.

In some embodiments, each occurrence of R³⁴ is independently selectedfrom the group consisting of H and C₁-C₅alkyl, wherein C₁-C₅alkyl may beoptionally substituted by one, two, or three independent occurrences offluorine. In some embodiments, two R³⁴ are joined together with thecarbon to which they are attached to form C₃-C₆cycloalkyl.

In some embodiments, Z is selected from the group consisting of:

In some embodiments, Z is selected from the group consisting of:

In some embodiments, n is 3.

In an embodiment, the compound is represented by a formula selected fromthe group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁹ is independentlyselected from the group consisting of H, C₁-C₃alkyl, andC₃-C₅cycloalkyl; each occurrence of R³⁴ is selected from the groupconsisting of H, C₁-C₂alkyl, and C₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁹ is selected from H and C₁-C₃alkyl;each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3. In some embodiments, eachoccurrence of R¹ is bromo; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is selected from H and C₁-C₃alkyl; each R³⁴ is H; and nis 3.

In some embodiments, each occurrence of R¹ is CF₃; each occurrence of R²is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, andchloro; each occurrence of R⁹ is independently selected from H andC₁-C₃alkyl; each occurrence of R³⁴ is independently selected from thegroup consisting of H and C₁-C₂alkyl; and n is 3. In some embodiments,each occurrence of R¹ is CF₃; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is independently selected from H and C₁-C₃alkyl; eachR³⁴ is H; and n is 3.

In some embodiments, each occurrence of R¹ is CF₂H; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁹ is selected from H and C₁-C₃alkyl;each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3 In some embodiments, eachoccurrence of R¹ is CF₂H; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is selected from H and C₁-C₃alkyl; each R³⁴ is H; and nis 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁶ is independentlyselected from C₁-C₃alkyl and C₃-C₄cycloalkyl; each occurrence of R⁹ isindependently selected from the group consisting of H, C₁-C₃alkyl, andC₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ is selectedfrom C₁-C₃alkyl and C₃-C₄cycloalkyl; each occurrence of R⁹ is selectedfrom H and C₁-C₃alkyl; and n is 3. In some embodiments, each occurrenceof R¹ is CF₃; each occurrence of R² is independently selected fromC₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from C₁-C₃alkyl and C₃-C₄cycloalkyl; eachoccurrence of R⁹ is independently selected from H and C₁-C₃alkyl; and nis 3. In some embodiments, each occurrence of R¹ is CF₂H; eachoccurrence of R² is independently selected from C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from C₁-C₃alkyl and C₃-C₄cycloalkyl; eachoccurrence of R⁹ is independently selected from H and C₁-C₃alkyl; and nis 3.

In an embodiment, the compound is represented by a formula selected fromthe group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁹ is independentlyselected from the group consisting of H, C₁-C₃alkyl, andC₃-C₅cycloalkyl; each occurrence of R³⁴ is selected from the groupconsisting of H, C₁-C₂alkyl, and C₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁹ is selected from H and C₁-C₃alkyl;each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3. In some embodiments, eachoccurrence of R¹ is bromo; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is selected from H and C₁-C₃alkyl; each R³⁴ is H; and nis 3.

In some embodiments, each occurrence of R¹ is CF₃; each occurrence of R²is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, andchloro; each occurrence of R⁹ is independently selected from H andC₁-C₃alkyl; each occurrence of R³⁴ is independently selected from thegroup consisting of H and C₁-C₂alkyl; and n is 3. In some embodiments,each occurrence of R¹ is CF₃; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is independently selected from H and C₁-C₃alkyl; eachR³⁴ is H; and n is 3.

In some embodiments, each occurrence of R¹ is CF₂H; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁹ is selected from H and C₁-C₃alkyl;each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3 In some embodiments, eachoccurrence of R¹ is CF₂H; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is selected from H and C₁-C₃alkyl; each R³⁴ is H; and nis 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁶ is independentlyselected from C₁-C₃alkyl and C₃-C₄cycloalkyl; each occurrence of R⁹ isindependently selected from the group consisting of H, C₁-C₃alkyl, andC₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁶ is selected from C₁-C₃alkyl andC₃-C₄cycloalkyl; each occurrence of R⁹ is selected from H andC₁-C₃alkyl; and n is 3. In some embodiments, each occurrence of R¹ isCF₃; each occurrence of R² is independently selected from C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from the group consisting of C₁-C₃alkyl andC₃-C₄cycloalkyl; each occurrence of R⁹ is independently selected from Hand C₁-C₃alkyl; and n is 3. In some embodiments, each occurrence of R¹is CF₂H; each occurrence of R² is independently selected fromC₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from the group consisting of C₁-C₃alkyl andC₃-C₄cycloalkyl; each occurrence of R⁹ is independently selected from Hand C₁-C₃alkyl; and n is 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R³⁴ is selected fromthe group consisting of H, C₁-C₂alkyl, and C₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R³⁴ is independently selected from thegroup consisting of H and C₁-C₂alkyl; and n is 3. In some embodiments,each occurrence of R¹ is bromo; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each R³⁴is H; and n is 3.

In some embodiments, each occurrence of R¹ is CF₃; each occurrence of R²is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, andchloro; each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3. In some embodiments, eachoccurrence of R¹ is CF₃; each occurrence of R² is independently selectedfrom C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each R³⁴ is H; andn is 3.

In some embodiments, each occurrence of R¹ is CF₂H; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R³⁴ is independently selected from thegroup consisting of H and C₁-C₂alkyl; and n is 3. In some embodiments,each occurrence of R¹ is CF₂H; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each R³⁴is H; and n is 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁶ is independentlyselected from C₁-C₃alkyl and C₃-C₄cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁶ is selected from C₁-C₃alkyl andC₃-C₄cycloalkyl; and n is 3. In some embodiments, each occurrence of R¹is CF₃; each occurrence of R² is independently selected from C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from C₁-C₃alkyl and C₃-C₄cycloalkyl; and n is 3.In some embodiments, each occurrence of R¹ is CF₂H; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁶ is independently selected fromC₁-C₃alkyl and C₃-C₄cycloalkyl; and n is 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁹ is independentlyselected from the group consisting of H, C₁-C₃alkyl, andC₃-C₅cycloalkyl; each occurrence of R³⁴ is selected from the groupconsisting of H, C₁-C₂alkyl, and C₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁹ is selected from H and C₁-C₃alkyl;each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3. In some embodiments, eachoccurrence of R¹ is bromo; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is selected from H and C₁-C₃alkyl; each R³⁴ is H; and nis 3.

In some embodiments, each occurrence of R¹ is CF₃; each occurrence of R²is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, andchloro; each occurrence of R⁹ is independently selected from H andC₁-C₃alkyl; each occurrence of R³⁴ is independently selected from thegroup consisting of H and C₁-C₂alkyl; and n is 3. In some embodiments,each occurrence of R¹ is CF₃; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is independently selected from H and C₁-C₃alkyl; eachR³⁴ is H; and n is 3.

In some embodiments, each occurrence of R¹ is CF₂H; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁹ is selected from H and C₁-C₃alkyl;each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3 In some embodiments, eachoccurrence of R¹ is CF₂H; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is selected from H and C₁-C₃alkyl; each R³⁴ is H; and nis 3.

In some embodiments, the compound is represented by a formula selectedfrom:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁶ is independentlyselected from C₁-C₃alkyl and C₃-C₄cycloalkyl; each occurrence of R⁹ isindependently selected from the group consisting of H, C₁-C₃alkyl, andC₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ is selectedfrom C₁-C₃alkyl and C₃-C₄cycloalkyl; each occurrence of R⁹ is selectedfrom H and C₁-C₃alkyl; and n is 3. In some embodiments, each occurrenceof R¹ is CF₃; each occurrence of R² is independently selected fromC₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from C₁-C₃alkyl and C₃-C₄cycloalkyl; eachoccurrence of R⁹ is independently selected from H and C₁-C₃alkyl; and nis 3. In some embodiments, each occurrence of R¹ is CF₂H; eachoccurrence of R² is independently selected from C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from C₁-C₃alkyl and C₃-C₄cycloalkyl; eachoccurrence of R⁹ is independently selected from H and C₁-C₃alkyl; and nis 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R³⁴ is selected fromthe group consisting of H, C₁-C₂alkyl, and C₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R³⁴ is independently selected from thegroup consisting of H and C₁-C₂alkyl; and n is 3. In some embodiments,each occurrence of R¹ is bromo; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each R³⁴is H; and n is 3.

In some embodiments, each occurrence of R¹ is CF₃; each occurrence of R²is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, andchloro; each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3. In some embodiments, eachoccurrence of R¹ is CF₃; each occurrence of R² is independently selectedfrom C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each R³⁴ is H; andn is 3.

In some embodiments, each occurrence of R¹ is CF₂H; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R³⁴ is independently selected from thegroup consisting of H and C₁-C₂alkyl; and n is 3. In some embodiments,each occurrence of R¹ is CF₂H; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each R³⁴is H; and n is 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁶ is independentlyselected from C₁-C₃alkyl and C₃-C₄cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁶ is selected from C₁-C₃alkyl andC₃-C₄cycloalkyl; and n is 3. In some embodiments, each occurrence of R¹is CF₃; each occurrence of R² is independently selected from C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from C₁-C₃alkyl and C₃-C₄cycloalkyl; and n is 3.In some embodiments, each occurrence of R¹ is CF₂H; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁶ is independently selected fromC₁-C₃alkyl and C₃-C₄cycloalkyl; and n is 3.

In some embodiments, the compound is represented by:

wherein R¹ is selected from the group consisting of bromo, chloro, CF₃,CF₂H, and cyclopropyl; R² is selected from the group consisting ofC₁-C₂alkyl, C₃-C₄cycloalkyl, and halogen; and R⁹ is selected from thegroup consisting of C₁-C₃alkyl, H, and C₃-C₅cycloalkyl. In someembodiments, R¹ is CF₃; R² is selected from the group consisting ofC₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; and R⁹ is selected fromC₁-C₃alkyl and H. In some embodiments, R¹ is bromo; R² is selected fromthe group consisting of C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro;and R⁹ is selected from C₁-C₃alkyl and H. In some embodiments, R¹ isCF₂H; R² is selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; and R⁹ is selected from C₁-C₃alkyland H.

In some embodiments, the compound is represented by:

wherein R¹ is selected from the group consisting of bromo, chloro, CF₃,CF₂H, and cyclopropyl; R² is selected from the group consisting ofC₁-C₂alkyl, C₃-C₄cycloalkyl, and halogen; and R⁹ is selected from thegroup consisting of C₁-C₃alkyl, H, and C₃-C₅cycloalkyl. In someembodiments, R¹ is CF₃; R² is selected from the group consisting ofC₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; and R⁹ is selected fromC₁-C₃alkyl and H. In some embodiments, R¹ is bromo; R² is selected fromthe group consisting of C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro;and R⁹ is selected from C₁-C₃alkyl and H. In some embodiments, R¹ isCF₂H; R² is selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; and R⁹ is selected from C₁-C₃alkyland H.

In some embodiments, the compound is represented by:

wherein R¹ is selected from the group consisting of bromo, chloro, CF₃,CF₂H, and cyclopropyl; R² is selected from the group consisting ofC₁-C₂alkyl, C₃-C₄cycloalkyl, and halogen; and R⁹ is selected from thegroup consisting of C₁-C₃alkyl, H, and C₃-C₅cycloalkyl. In someembodiments, R¹ is CF₃; R² is selected from the group consisting ofC₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; and R⁹ is selected fromC₁-C₃alkyl and H. In some embodiments, R¹ is bromo; R² is selected fromthe group consisting of C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro;and R⁹ is selected from C₁-C₃alkyl and H. In some embodiments, R¹ isCF₂H; R² is selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; and R⁹ is selected from C₁-C₃alkyland H.

In some embodiments, the compound is represented by:

wherein R¹ is selected from the group consisting of bromo, chloro, CF₃,CF₂H, and cyclopropyl; R² is selected from the group consisting ofC₁-C₂alkyl, C₃-C₄cycloalkyl, and halogen; and R⁹ is selected from thegroup consisting of C₁-C₃alkyl, H, and C₃-C₅cycloalkyl. In someembodiments, R¹ is CF₃; R² is selected from the group consisting ofC₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; and R⁹ is selected fromC₁-C₃alkyl and H. In some embodiments, R¹ is bromo; R² is selected fromthe group consisting of C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro;and R⁹ is selected from C₁-C₃alkyl and H. In some embodiments, R¹ isCF₂H; R² is selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; and R⁹ is selected from C₁-C₃alkyland H.

In some embodiments, the compound is represented by:

wherein R¹ is selected from the group consisting of bromo, chloro, CF₃,CF₂H, and cyclopropyl; R² is selected from the group consisting ofC₁-C₂alkyl, C₃-C₄cycloalkyl, and halogen; and R⁹ is selected from thegroup consisting of C₁-C₃alkyl, H, and C₃-C₅cycloalkyl. In someembodiments, R¹ is CF₃; R² is selected from the group consisting ofC₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; and R⁹ is selected fromC₁-C₃alkyl and H. In some embodiments, R¹ is bromo; R² is selected fromthe group consisting of C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro;and R⁹ is selected from C₁-C₃alkyl and H. In some embodiments, R¹ isCF₂H; R² is selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; and R⁹ is selected from C₁-C₃alkyland H.

In some embodiments, the compound is represented by:

wherein R¹ is selected from the group consisting of bromo, chloro, CF₃,CF₂H, and cyclopropyl; and R² is selected from the group consisting ofC₁-C₂alkyl, C₃-C₄cycloalkyl, and halogen. In some embodiments, R¹ isCF₃; and R² is selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro. In some embodiments, R¹ is bromo;and R² is selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro. In some embodiments, R¹ is CF₂H; andR² is selected from the group consisting of C₁-C₂alkyl, C₃-C₄cycloalkyl,bromo, and chloro.

In some embodiments, the compound is represented by:

wherein R¹ is selected from the group consisting of bromo, chloro, CF₃,CF₂H, and cyclopropyl; and R² is selected from the group consisting ofC₁-C₂alkyl, C₃-C₄cycloalkyl, and halogen. In some embodiments, R¹ isCF₃; and R² is selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro. In some embodiments, R¹ is bromo;and R² is selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro. In some embodiments, R¹ is CF₂H; andR² is selected from the group consisting of C₁-C₂alkyl, C₃-C₄cycloalkyl,bromo, and chloro.

In some embodiments, the compound is represented by:

or a pharmaceutically acceptable salt thereof, wherein: n is 2, 3, or 4;R¹ is selected from the group consisting of halogen, cyano, C₁-C₅alkyl,and C₃-C₅cycloalkyl, wherein each C₁-C₅alkyl and C₃-C₅cycloalkyl may beoptionally substituted by one, two or three independent occurrences offluorine; R¹ is selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; R⁴ is selected from the group consistingof:

each occurrence of R⁶ and R⁹ is independently selected from the groupconsisting of H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C(═O)R⁵, SO₂R⁵, and D,wherein each C₁-C₆alkyl and C₃-C₆cycloalkyl may be optionallysubstituted by one or more independent occurrences of fluorine; eachoccurrence of R⁵ is independently selected from the group consisting ofH, C₁-C₆alkyl, C₃-C₆cycloalkyl, and heterocyclyl, wherein eachC₁-C₆alkyl and C₃-C₆cycloalkyl may be optionally substituted by one ormore independent occurrences of fluorine; each occurrence of R⁷ isindependently selected from the group consisting of H, C₁-C₆ alkyl, andC₃-C₆cycloalkyl, wherein each C₁-C₆alkyl and C₃-C₆cycloalkyl may beoptionally substituted by one or more independent occurrences offluorine, or two R⁷ are joined together with the atom to which they areattached to form oxo; D is selected from a C-linked heterocyclyl havingat least one nitrogen and optionally having an additional ring nitrogenor oxygen and heteroaryl, wherein D may be optionally substituted on oneor more available carbons by R⁷ and may be optionally substituted on anavailable nitrogen by R⁹; Z is selected from the group consisting of:

and each occurrence of R³⁴ is independently selected from H and R³⁶,wherein each occurrence of R³⁶ is independently selected from C₁-C₆alkyland C₃-C₆cycloalkyl, wherein each C₁-C₅alkyl and C₃-C₆cycloalkyl may beoptionally substituted by one or more independent occurrences offluorine, or two R³⁶ are joined together with the carbon to which theyare attached to form a C₃-C₆cycloalkyl.

In some embodiments, R¹ is selected from the group consisting ofhalogen, C₁-C₅alkyl, and C₃-C₅cycloalkyl, wherein C₁-C₅alkyl may beoptionally substituted with one, two, or three occurrences of fluorine,and C₃-C₅cycloalkyl. In some embodiments, R¹ is CF₃. In someembodiments, R¹ is CF₂H. In some embodiments, R¹ is halogen. In someembodiments, R¹ is bromo. In some embodiments, R¹ is cyclopropyl.

In some embodiments, R² is selected from the group consisting of H,C₃-C₄cycloalkyl, C₁-C₅alkyl, and halogen. In some embodiments, R² isselected from the group consisting of C₁-C₂alkyl, C₃-C₄cycloalkyl,bromo, anc chloro.

In some embodiments, R⁴ is selected from the group consisting of:

In some embodiments, R⁴ is selected from the group consisting of:

In some embodiments, each R⁶ and R⁹ is independently selected from thegroup consisting of H, C₁-C₆alkyl, and C₃-C₆cycloalkyl, wherein each ofC₁-C₆alkyl and C₃-C₆cycloalkyl is optionally substituted by one or moreindependent occurrences of fluorine.

In some embodiments, R⁷ is H.

In some embodiments, R³⁴ is selected from the group consisting of H andC₁-C₅alkyl, wherein C₁-C₅alkyl may be optionally substituted by one,two, or three independent occurrences of fluorine. In some embodiments,two R³⁴ are joined together with the carbon to which they are attachedto form C₃-C₆cycloalkyl;

In some embodiments, Z is selected from the group consisting of:

In some embodiments, Z is selected from the group consisting of:

In some embodiments, n is 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁹ is independentlyselected from the group consisting of H, C₁-C₃alkyl, andC₃-C₅cycloalkyl; each occurrence of R³⁴ is selected from the groupconsisting of H, C₁-C₂alkyl, and C₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁹ is selected from H and C₁-C₃alkyl;each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3. In some embodiments, eachoccurrence of R¹ is bromo; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is selected from H and C₁-C₃alkyl; each R³⁴ is H; and nis 3.

In some embodiments, each occurrence of R¹ is CF₃; each occurrence of R²is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, andchloro; each occurrence of R⁹ is independently selected from H andC₁-C₃alkyl; each occurrence of R³⁴ is independently selected from thegroup consisting of H and C₁-C₂alkyl; and n is 3. In some embodiments,each occurrence of R¹ is CF₃; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is independently selected from H and C₁-C₃alkyl; eachR³⁴ is H; and n is 3.

In some embodiments, each occurrence of R¹ is CF₂H; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁹ is selected from H and C₁-C₃alkyl;each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3 In some embodiments, eachoccurrence of R¹ is CF₂H; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is selected from H and C₁-C₃alkyl; each R³⁴ is H; and nis 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁶ is independentlyselected from C₁-C₃alkyl and C₃-C₄cycloalkyl; each occurrence of R⁹ isindependently selected from the group consisting of H, C₁-C₃alkyl, andC₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ is selectedfrom C₁-C₃alkyl and C₃-C₄cycloalkyl; each occurrence of R⁹ is selectedfrom H and C₁-C₃alkyl; and n is 3. In some embodiments, each occurrenceof R¹ is CF₃; each occurrence of R² is independently selected fromC₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from C₁-C₃alkyl and C₃-C₄cycloalkyl; eachoccurrence of R⁹ is independently selected from H and C₁-C₃alkyl; and nis 3. In some embodiments, each occurrence of R¹ is CF₂H; eachoccurrence of R² is independently selected from C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from C₁-C₃alkyl and C₃-C₄cycloalkyl; eachoccurrence of R⁹ is independently selected from H and C₁-C₃alkyl; and nis 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁹ is independentlyselected from the group consisting of H, C₁-C₃alkyl, andC₃-C₅cycloalkyl; each occurrence of R³⁴ is selected from the groupconsisting of H, C₁-C₂alkyl, and C₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁹ is selected from H and C₁-C₃alkyl;each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3. In some embodiments, eachoccurrence of R¹ is bromo; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is selected from H and C₁-C₃alkyl; each R³⁴ is H; and nis 3.

In some embodiments, each occurrence of R¹ is CF₃; each occurrence of R²is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, andchloro; each occurrence of R⁹ is independently selected from H andC₁-C₃alkyl; each occurrence of R³⁴ is independently selected from thegroup consisting of H and C₁-C₂alkyl; and n is 3. In some embodiments,each occurrence of R¹ is CF₃; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is independently selected from H and C₁-C₃alkyl; eachR³⁴ is H; and n is 3.

In some embodiments, each occurrence of R¹ is CF₂H; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁹ is selected from H and C₁-C₃alkyl;each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3 In some embodiments, eachoccurrence of R¹ is CF₂H; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is selected from H and C₁-C₃alkyl; each R³⁴ is H; and nis 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁶ is independentlyselected from C₁-C₃alkyl and C₃-C₄cycloalkyl; each occurrence of R⁹ isindependently selected from the group consisting of H, C₁-C₃alkyl, andC₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁶ is selected from C₁-C₃alkyl andC₃-C₄cycloalkyl; each occurrence of R⁹ is selected from H andC₁-C₃alkyl; and n is 3. In some embodiments, each occurrence of R¹ isCF₃; each occurrence of R² is independently selected from C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from the group consisting of C₁-C₃alkyl andC₃-C₄cycloalkyl; each occurrence of R⁹ is independently selected from Hand C₁-C₃alkyl; and n is 3. In some embodiments, each occurrence of R¹is CF₂H; each occurrence of R² is independently selected fromC₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from the group consisting of C₁-C₃alkyl andC₃-C₄cycloalkyl; each occurrence of R⁹ is independently selected from Hand C₁-C₃alkyl; and n is 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R³⁴ is selected fromthe group consisting of H, C₁-C₂alkyl, and C₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R³⁴ is independently selected from thegroup consisting of H and C₁-C₂alkyl; and n is 3. In some embodiments,each occurrence of R¹ is bromo; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each R³⁴is H; and n is 3.

In some embodiments, each occurrence of R¹ is CF₃; each occurrence of R²is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, andchloro; each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3. In some embodiments, eachoccurrence of R¹ is CF₃; each occurrence of R² is independently selectedfrom C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each R³⁴ is H; andn is 3.

In some embodiments, each occurrence of R¹ is CF₂H; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R³⁴ is independently selected from thegroup consisting of H and C₁-C₂alkyl; and n is 3. In some embodiments,each occurrence of R¹ is CF₂H; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each R³⁴is H; and n is 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁶ is independentlyselected from C₁-C₃alkyl and C₃-C₄cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁶ is selected from C₁-C₃alkyl andC₃-C₄cycloalkyl; and n is 3. In some embodiments, each occurrence of R¹is CF₃; each occurrence of R² is independently selected from C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from C₁-C₃alkyl and C₃-C₄cycloalkyl; and n is 3.In some embodiments, each occurrence of R¹ is CF₂H; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁶ is independently selected fromC₁-C₃alkyl and C₃-C₄cycloalkyl; and n is 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁹ is independentlyselected from the group consisting of H, C₁-C₃alkyl, andC₃-C₅cycloalkyl; each occurrence of R³⁴ is selected from the groupconsisting of H, C₁-C₂alkyl, and C₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁹ is selected from H and C₁-C₃alkyl;each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3. In some embodiments, eachoccurrence of R¹ is bromo; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is selected from H and C₁-C₃alkyl; each R³⁴ is H; and nis 3.

In some embodiments, each occurrence of R¹ is CF₃; each occurrence of R²is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, andchloro; each occurrence of R⁹ is independently selected from H andC₁-C₃alkyl; each occurrence of R³⁴ is independently selected from thegroup consisting of H and C₁-C₂alkyl; and n is 3. In some embodiments,each occurrence of R¹ is CF₃; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is independently selected from H and C₁-C₃alkyl; eachR³⁴ is H; and n is 3.

In some embodiments, each occurrence of R¹ is CF₂H; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁹ is selected from H and C₁-C₃alkyl;each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3 In some embodiments, eachoccurrence of R¹ is CF₂H; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; eachoccurrence of R⁹ is selected from H and C₁-C₃alkyl; each R³⁴ is H; and nis 3.

In some embodiments, the compound is represented by a formula selectedfrom:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁶ is independentlyselected from C₁-C₃alkyl and C₃-C₄cycloalkyl; each occurrence of R⁹ isindependently selected from the group consisting of H, C₁-C₃alkyl, andC₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ is selectedfrom C₁-C₃alkyl and C₃-C₄cycloalkyl; each occurrence of R⁹ is selectedfrom H and C₁-C₃alkyl; and n is 3. In some embodiments, each occurrenceof R¹ is CF₃; each occurrence of R² is independently selected fromC₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from C₁-C₃alkyl and C₃-C₄cycloalkyl; eachoccurrence of R⁹ is independently selected from H and C₁-C₃alkyl; and nis 3. In some embodiments, each occurrence of R¹ is CF₂H; eachoccurrence of R² is independently selected from C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from C₁-C₃alkyl and C₃-C₄cycloalkyl; eachoccurrence of R⁹ is independently selected from H and C₁-C₃alkyl; and nis 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R³⁴ is selected fromthe group consisting of H, C₁-C₂alkyl, and C₃-C₅cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R³⁴ is independently selected from thegroup consisting of H and C₁-C₂alkyl; and n is 3. In some embodiments,each occurrence of R¹ is bromo; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each R³⁴is H; and n is 3.

In some embodiments, each occurrence of R¹ is CF₃; each occurrence of R²is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, andchloro; each occurrence of R³⁴ is independently selected from the groupconsisting of H and C₁-C₂alkyl; and n is 3. In some embodiments, eachoccurrence of R¹ is CF₃; each occurrence of R² is independently selectedfrom C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each R³⁴ is H; andn is 3.

In some embodiments, each occurrence of R¹ is CF₂H; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R³⁴ is independently selected from thegroup consisting of H and C₁-C₂alkyl; and n is 3. In some embodiments,each occurrence of R¹ is CF₂H; each occurrence of R² is independentlyselected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; each R³⁴is H; and n is 3.

In some embodiments, the compound is represented by a formula selectedfrom the group consisting of:

wherein each occurrence of R¹ is independently selected from the groupconsisting of bromo, chloro, CF₃, CF₂H, and cyclopropyl; each occurrenceof R² is independently selected from the group consisting of C₁-C₂alkyl,C₃-C₄cycloalkyl, and halogen; each occurrence of R⁶ is independentlyselected from C₁-C₃alkyl and C₃-C₄cycloalkyl; and n is 3.

In some embodiments, each occurrence of R¹ is bromo; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁶ is selected from C₁-C₃alkyl andC₃-C₄cycloalkyl; and n is 3. In some embodiments, each occurrence of R¹is CF₃; each occurrence of R² is independently selected from C₁-C₂alkyl,C₃-C₄cycloalkyl, bromo, and chloro; each occurrence of R⁶ isindependently selected from C₁-C₃alkyl and C₃-C₄cycloalkyl; and n is 3.In some embodiments, each occurrence of R¹ is CF₂H; each occurrence ofR² is independently selected from C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo,and chloro; each occurrence of R⁶ is independently selected fromC₁-C₃alkyl and C₃-C₄cycloalkyl; and n is 3.

In an embodiment, described herein is a compound selected from the groupconsisting of:1-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-cyclopropyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((5-chloro-2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,(R)-1-(3-ethyl-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyrrolidine-3-carbonitrile,1-(3-((2-((4-(4-cyclopropylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-ethyl-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,4-(3-cyclopropyl-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1-methylpiperazin-2-one,1-(3-((5-bromo-2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((5-chloro-2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-cyclopropyl-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(4-(2-fluoroethyl)piperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((5-chloro-2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(4-acetylpiperazin-1-yl)-2-cyclopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,(S)-1-(3-ethyl-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyrrolidine-3-carbonitrile,1-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(4-isopropylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(4-cyclobutylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-cyclopropyl-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-ethyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(4-ethyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-methyl-6-morpholinopyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,3-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,rac-(R)-3-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,rac-(R)-3-(3-((2-((2-cyclopropyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-ethyl-4-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)morpholin-3-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one,4-(3-((2-((2-ethyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-cyclopropyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-chloro-2-((2-ethyl-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-chloro-2-((2-cyclopropyl-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,rac-4-(3-((2-((4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-chloro-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-chloro-2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,rac-(R)-4-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one,4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-((3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one,1-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-methyl-6-morpholinopyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one,4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,1-(3-((5-cyclopropyl-2-((4-(4-cyclopropylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-5,5-dimethylpyrrolidin-2-one,1-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((2-((4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one,4-(3-((2-((4-ethyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((4-ethyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,(R)-4-(3-((2-((2-cyclopropyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,4-(3-((2-((2-cyclopropyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((2-cyclopropyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,4-(3-((2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,1-(3-((2-((2-cyclopropyl-4-(3-(dimethylamino)azetidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,4-(3-((2-((2-(methoxymethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((4-ethyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile,3-(3-((2-((2-cyclopropyl-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,(S)-2-(4-(3-ethyl-4-((4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1-methylpiperazin-2-yl)acetonitrile,(R)-2-(4-(3-ethyl-4-((4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1-methylpiperazin-2-yl)acetonitrile,(S)-2-(1-methyl-4-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-2-yl)acetonitrile,(R)-2-(1-methyl-4-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-2-yl)acetonitrile,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3434(5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,4-(3-((2-((2-ethyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-(9-methyl-3,9-diazabicyclo[3.3.1]nonan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-(3-methyl-3,9-diazabicyclo[3.3.1]nonan-9-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,(S)-4-(3-((2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,(R)-4-(3-((2-((4-(3-(dimethylamino)pyrrolidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-(1-methylpyrrolidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethynyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-(ethynyl-d)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-(ethyl-d5)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(2,2,2-trifluoroethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-(1,1-difluoroethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,5-(4-methylpiperazin-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzonitrile,2-methyl-2-(5-(4-methylpiperazin-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)propanenitrile,2-(5-(4-methylpiperazin-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)acetonitrile,4-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-(difluoromethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(3-(dimethylamino)azetidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(3-((dimethylamino)methyl)azetidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one,3-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one,3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one,1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one,4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one,1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one,3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,(R)-3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,(S)-3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one,3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one,1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one,1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,24(2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-(1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,(R)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,(S)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(4-methyl-2-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(4-methyl-7-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(4-methyl-7-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxo-1,3-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxo-1,3-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile,1-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one,4-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one,3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one,4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one,3-((3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one,4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one,8-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-5-oxa-8-azaspiro[2.6]nonan-9-one,4-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one,4-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one,4-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one,1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one,1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one,1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one,1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one,1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one,1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one,1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one,1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one,1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one,1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one,1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one,1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one,1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one,1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one,1-(3-((5-chloro-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((5-chloro-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-chloropyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((5-chloro-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((5-bromo-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((5-bromo-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-bromopyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((5-bromo-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,4-(3-((2-((4-(3-(diethylamino)propyl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(3-morpholinopropyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,3-(3-((2-((2-ethyl-4-(2-(pyrrolidin-1-yl)ethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-cyclopropyl-4-((dimethylamino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-methoxy-N-(1-methylpiperidin-4-yl)-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide,4-(3-((2-((4-(4-(diethylamino)piperidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,(S)-4-(3-((2-((2-cyclopropyl-4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,1-(3-((2-((2-cyclopropyl-4-(morpholinomethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-ethyl-4-(2-(pyrrolidin-1-yl)propan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,4-(3-((2-((2-ethyl-4-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((4-(4-((dimethylamino)methyl)piperidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((4-(4-(dimethylglycyl)piperazin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((4-(3,3-dimethylpiperazin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-4-(3,3,5,5-tetramethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-cyclopropyl-4-(3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-(3,3,4-trimethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-4-(3,3,4,5,5-pentamethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,1-(3-((2-((2-chloro-4-(3,4-dimethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one,3-(3-((2-((4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazepan-2-one,4-(3-((2-((4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((4-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one,3-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazepan-2-one,4-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazepan-2-one,4-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,1-(3-((2-((4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)azepan-2-one,1-(3-((2-((2-cyclopropyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(difluoromethyl)pyridin-4-yl)amino)propyl)pyrrolidin-2-one,4-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-methyl-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((4-(4-(dimethylglycyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,1-(3-((2-((2-cyclopropyl-4-(morpholinomethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one,3-(3-((2-((2-ethyl-4-(2-(pyrrolidin-1-yl)ethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-fluoro-4-(3-morpholinopropyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one,1-(3-((2-((2-cyclopropyl-4-((1,1-dioxidothiomorpholino)methyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-cyclopropyl-4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one,3-(3-((2-((4-(3-(diethylamino)propyl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one,4-(3-((2-((2-chloro-4-(3,4-dimethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,1-(3-((2-((2-cyclopropyl-4-(morpholinosulfonyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one,3-(3-((2-((2-(2-hydroxypropan-2-yl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,4-(3-((2-((2-(2-hydroxypropan-2-yl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-(1-hydroxyethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-methyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-chloro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-(1-hydroxyethyl)-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-chloro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-(1-hydroxyethyl)-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-methyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-chloro-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-(1-hydroxyethyl)-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-(1-hydroxyethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-chloro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-(1-hydroxyethyl)-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-chloro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-(1-hydroxyethyl)-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-methyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-chloro-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-(1-hydroxyethyl)-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,4-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-(1-hydroxyethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-methyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-chloro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-(1-hydroxyethyl)-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-(difluoromethoxy)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((2-(methoxymethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one,4-(3-((2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,1-(3-((2-((2-cyclopropyl-4-(3-((dimethylamino)methyl)azetidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,4-(3-((2-((4-(3-((dimethylamino)methyl)azetidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,and pharmaceutically acceptable salts, enantiomers, stereoisomers, andtautomers thereof.

Methods of Treatment

Compounds described herein can act as inhibitors of autophagy useful inthe treatment of a disorder in a patient in need thereof. The disorder,for example, can be a tumor, e.g., a solid tumor. The disorder may alsobe cancer.

Exemplary disorders also include gastrointestinal stromal tumors,esophageal cancer, gastric cancer, melanomas, gliomas, glioblastomas,ovarian cancer, bladder cancer, pancreatic cancer, prostate cancer, lungcancers, breast cancers, renal cancers, hepatic cancers, osteosarcomas,multiple myelomas, cervical carcinomas, cancers that are metastatic tobone, papillary thyroid carcinoma, non-small cell lung cancer, andcolorectal cancers. A cancer treated by the methods described herein maybe a metastatic cancer.

In some embodiments, the compounds described herein are useful for thetreatment of cancers caused by RAS mutation. In some embodiments, thecancer is caused by a KRAS mutation. In some embodiments, the cancer hasadditional mutations in tumor suppressor proteins, including mutationsin TP53, PTEN, CDN2A/INK4A, p16, or STAG2. In some embodiments, theseadditional mutations occur in one or more of TP53, PTEN, CDN2A/INK4A,p16, or STAG2. In some embodiments, the cancer is pancreatic ductaladenocarcinoma. In some embodiments, the cancer is lung cancer. In someembodiments, the cancer is colorectal.

In some embodiments, determination of cellular inhibition of autophagyby compounds described herein is determined by monitoring of autophagicflux, for instance by monitoring inhibition of autophagy-mediatedclearance of mCherry/GFP-LC3 fusion protein. In some embodiments,determination of cellular inhibition of autophagy by compounds describedherein is determined by monitoring of accumulation of autophagicproteins such as p62 or LC-3. In some embodiments, determination ofcellular inhibition of autophagy by compounds described herein isdetermined by decreased clearance of luciferase-tagged LC3 protein. Insome embodiments, determination of cellular inhibition of autophagy bycompounds described herein is determined by monitoring decreases incellular autophagosomes, for instance by measurement of fluorescentpuncta with the autophagosome marker Cyto-ID.

In some embodiments, cellular inhibition of ULK kinase by compoundsdescribed herein is determined by inhibition of phosphorylation ofcellular ULK substrates including ATG13, ATG14, Beclin 1, or STINGeither in tumor cells or in non-tumor host tissues. In some embodiments,cellular inhibition of ULK kinase by compounds described herein isdetermined in host tissues including immune cells.

In some embodiments, in vivo inhibition of autophagy by compoundsdescribed herein is determined by inhibition of phosphorylation ofcellular ULK substrates including ATG13, ATG14, Beclin 1, or STINGeither in tumor cells or in non-tumor host tissues. In some embodiments,in vivo inhibition of ULK kinase by compounds described herein isdetermined in host tissues including immune cells. In some embodiments,the in vivo inhibition of autophagic flux by compounds described hereincan be used as a pharmacodynamic model for monitoring the kinetics andextent of such ULK inhibition. In some embodiments, tin vivo inhibitionof ULK kinase by compounds described herein is determined in pancreaticcancer-bearing animals. In some embodiments, in vivo inhibition of ULKkinase by compounds described herein is determined in lungcancer-bearing animals. In some embodiments, in vivo inhibition of ULKkinase is determined in colorectal cancer-bearing animals. In someembodiments, in vivo inhibition of autophagy by compounds describedherein is determined by inhibition of autophagic flux in tumor cells, orin non-tumor host tissues by monitoring inhibition of autophagosomeformation, or by accumulation of autophagic proteins such as p62 orLC-III. In some embodiments, in vivo inhibition of autophagy isdetermined in host tissues including immune cells. In some embodiments,the in vivo inhibition of autophagic flux can be used as apharmacodynamic model for monitoring the kinetics and extent of such ULKinhibition.

In some embodiments, inhibition of autophagy and anti-tumor activity bycompounds described herein are evaluated in xenograft studies utilizinghuman RAS mutant cell lines in immunocompromised mice, for instance inSCID or nude mice. In some embodiments, inhibition of autophagy andanti-tumor activity by compounds described herein are evaluated inxenograft studies utilizing human RAS mutant patient-derived tumorxenografts (PDXs) in immunocompromised mice, for instance in SCID ornude mice. In some embodiments, xenograft studies include evaluation ofcompounds described herein in pancreatic cancer models. In someembodiments, inhibition of autophagy and anti-tumor activity bycompounds described herein are evaluated in syngeneic murine geneticallyengineered models (GEMs) of mutant RAS cancers. In some embodiments,inhibition of autophagy and anti-tumor activity by compounds describedherein are evaluated in the murine GEM syngeneic orthotopic pancreaticcancer model known as the KPC model(LSL-Kras^(G12D/+);LSL-Trp53^(R172H/+);pdx-1-Cre) or variants of the KPCmodel.

In some embodiments, compounds described herein will be evaluated inxenograft or GEM cancer models in combination with a MEK inhibitor. Insome embodiments, compounds described herein will be evaluated inxenograft or GEM cancer models in combination with a RAF inhibitor. Insome embodiments, compounds described herein will be evaluated inxenograft or GEM cancer models in combination with an ERK inhibitor. Insome embodiments, compounds described herein will be evaluated inxenograft or GEM cancer models in combination with a RAS G12C directinhibitor.

In some embodiments, inhibition of autophagy and anti-tumor activity bycompounds described herein is evaluated in immunocompetent murine cancermodels to assess an immunomodulatory component to the mechanism ofaction of ULK inhibitors. In some embodiments, the immunocompetentmurine model is the murine GEM syngeneic orthotopic pancreatic cancermodel known as the KPC model (LSL-Kras^(G12D/+);LSL-Trp53^(R172H/+);Pdx-1-Cre) or variants of the KPC model. In some embodiments,immunomodulatory properties of compounds described herein are evaluatedin combination with a MEK inhibitor. In some embodiments,immunomodulatory properties of compounds described herein are evaluatedin combination with a RAF inhibitor. In some embodiments,immunomodulatory properties of compounds described herein are evaluatedin combination with an ERK inhibitor. In some embodiments,immunomodulatory properties of compounds described herein are evaluatedin combination with a RAS G12C direct inhibitor.

In some embodiments, the immunomodulatory component of ULK inhibition isan enhanced innate immune response. In some embodiments, theimmunomodulatory component of ULK inhibition is an enhanced adaptiveimmune response. In some embodiments, the immunomodulatory component ofULK inhibition is an enhanced activity of antigen-presenting cells. Insome embodiments, the immunomodulatory component of ULK inhibition is anenhanced anti-tumor activity of myeloid cells including macrophages. Insome embodiments, the immunomodulatory component of ULK inhibition is anenhanced anti-tumor activity of Natural Killer cells. In someembodiments, the immunomodulatory component of ULK inhibition is anenhanced activity of effector T Cells, including cytotoxic T Cells.

In an embodiment, provided herein is a method of treating a disorderdescribed herein that includes: administering a therapeuticallyeffective amount of compound described herein in a patient in needthereof, and during or after the course of administration (e.g., atdiscrete time points, such as one week, two weeks, or on month afterinitial administration of a contemplated compound) detecting theengagement of the compound with an ULK kinase, wherein detectingcomprises contacting a sample obtained from the patient (including butnot limited to a tumor, blood, saliva, or tissue) with a phospho-ATG13antibody ELISA assay to detect inhibition of ULK kinase activity, e.g,based on the level of phospho-ATG13 in the sample. In some embodiments,a contemplated method comprises optionally contacting a sample obtainedfrom the patient (including but not limited to a tumor, blood, saliva,or tissue) prior to administration of the compound with a phospho-ATG13antibody ELISA assay, and comparing the level of phospho-ATG13 in thesample obtained prior to administration with the level of phospho-ATG13in the sample obtained during or after the course of administration. Insome embodiments, the phospho-ATG13 is p-S318ATG13.

In an embodiment, provided herein is a method of treating a disorderdescribed herein that includes: administering a therapeuticallyeffective amount of compound described herein in a patient in needthereof, and during or after the course of administration (e.g., atdiscrete time points, such as one week, two weeks, or on month afterinitial administration of a contemplated compound) detecting theengagement of the compound with an ULK kinase, wherein detectingcomprises contacting a sample obtained from the patient (including butnot limited to a tumor, blood, saliva, or tissue) with a phospho-ATG14antibody ELISA assay to detect inhibition of ULK kinase activity, e.g,based on the level of phospho-ATG14 in the sample. In some embodiments,a contemplated method comprises optionally contacting a sample obtainedfrom the patient (including but not limited to a tumor, blood, saliva,or tissue) prior to administration of the compound with a phospho-ATG14antibody ELISA assay, and comparing the level of phospho-ATG14 in thesample obtained prior to administration with the level of phospho-ATG14in the sample obtained during or after the course of administration. Insome embodiments, the phospho-ATG14 is p-ATG14 Ser29.

In an embodiment, provided herein is a method of treating a disorderdescribed herein that includes: administering a therapeuticallyeffective amount of compound described herein in a patient in needthereof, and during or after the course of administration (e.g., atdiscrete time points, such as one week, two weeks, or on month afterinitial administration of a contemplated compound) detecting theengagement of the compound with an ULK kinase, wherein detectingcomprises contacting a sample obtained from the patient (including butnot limited to a tumor, blood, saliva, or tissue) with a p62 antibodyELISA assay to detect inhibition of ULK kinase activity, e.g, based onthe level of p62 in the sample. In some embodiments, a contemplatedmethod comprises optionally contacting a sample obtained from thepatient (including but not limited to a tumor, blood, saliva, or tissue)prior to administration of the compound with a p62 antibody ELISA assay,and comparing the level of p62 in the sample obtained prior toadministration with the level of p62 in the sample obtained during orafter the course of administration.

In an embodiment, provided herein is a method of treating a disorderdescribed herein that includes: administering a therapeuticallyeffective amount of compound described herein in a patient in needthereof, and during or after the course of administration (e.g., atdiscrete time points, such as one week, two weeks, or on month afterinitial administration of a contemplated compound) detecting theengagement of the compound with an ULK kinase, wherein detectingcomprises contacting a sample obtained from the patient (including butnot limited to a tumor, blood, saliva, or tissue) with a pBeclinantibody ELISA assay to detect inhibition of ULK kinase activity, e.g,based on the level of pBeclin in the sample. In some embodiments, acontemplated method comprises optionally contacting a sample obtainedfrom the patient (including but not limited to a tumor, blood, saliva,or tissue) prior to administration of the compound with a pBeclinantibody ELISA assay, and comparing the level of pBeclin in the sampleobtained prior to administration with the level of pBeclin in the sampleobtained during or after the course of administration.

The compounds provided herein may be administered to patients (animalsand humans) in need of such treatment in dosages that will provideoptimal pharmaceutical efficacy. It will be appreciated that the doserequired for use in any particular application will vary from patient topatient, not only with the particular compound or composition selected,but also with the route of administration, the nature of the conditionbeing treated, the age and condition of the patient, concurrentmedication or special diets then being followed by the patient, andother factors which those skilled in the art will recognize, with theappropriate dosage ultimately being at the discretion of the attendantphysician. For treating clinical conditions and diseases noted above, acompound provided herein may be administered orally, subcutaneously,topically, parenterally, by inhalation spray or rectally in dosage unitformulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. Parenteral administrationmay include subcutaneous injections, intravenous or intramuscularinjections or infusion techniques.

Treatment can be continued for as long or as short a period as desired.The compositions may be administered on a regimen of, for example, oneto four or more times per day. A suitable treatment period can be, forexample, at least about one week, at least about two weeks, at leastabout one month, at least about six months, at least about 1 year, orindefinitely. A treatment period can terminate when a desired result isachieved.

Combination Therapy

Compounds described herein, e.g., a compound of Formula I as definedherein, can be administered in combination with one or more additionaltherapeutic agents to treat a disorder described herein, such as cancer.For example, provided in the present disclosure is a pharmaceuticalcomposition comprising a compound described herein, e.g., a compound ofFormula I as defined herein, one or more additional therapeutic agents,and a pharmaceutically acceptable excipient. In some embodiments, acompound of Formula I as defined herein and one additional therapeuticagent is administered. In some embodiments, a compound of Formula I asdefined herein and two additional therapeutic agents are administered.In some embodiments, a compound of Formula I as defined herein and threeadditional therapeutic agents are administered. Combination therapy canbe achieved by administering two or more therapeutic agents, each ofwhich is formulated and administered separately. For example, a compoundof Formula I as defined herein and an additional therapeutic agent canbe formulated and administered separately. Combination therapy can alsobe achieved by administering two or more therapeutic agents in a singleformulation, for example a pharmaceutical composition comprising acompound of Formula I as one therapeutic agent and one or moreadditional therapeutic agents such as a MAPKAP pathway inhibitor orchemotherapeutic agent. For example, a compound of Formula I as definedherein and an additional therapeutic agent can be administered in asingle formulation. Other combinations are also encompassed bycombination therapy. While the two or more agents in the combinationtherapy can be administered simultaneously, they need not be. Forexample, administration of a first agent (or combination of agents) canprecede administration of a second agent (or combination of agents) byminutes, hours, days, or weeks. Thus, the two or more agents can beadministered within minutes of each other or within 1, 2, 3, 6, 9, 12,15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeksof each other. In some cases even longer intervals are possible. Whilein many cases it is desirable that the two or more agents used in acombination therapy be present in within the patient's body at the sametime, this need not be so.

Combination therapy can also include two or more administrations of oneor more of the agents used in the combination using different sequencingof the component agents. For example, if agent X and agent Y are used ina combination, one could administer them sequentially in any combinationone or more times, e.g., in the order X—Y—X, X—X—Y, Y—X—Y, Y—Y—X,X—X—Y—Y, etc.

In some embodiments, the one or more additional therapeutic agents thatmay be administered in combination with a compound provided herein canbe a MAPKAP pathway inhibitor. Such MAPKAP pathway inhibitors include,for example, MEK inhibitors, ERK inhibitors, RAF inhibitors, and Rasinhibitors.

Exemplary MEK inhibitors include, but are not limited to, trametinib,selumetinib, cobimetinib, binimetinib, and pharmaceutically acceptablesalts thereof. Exemplary ERK inhibitors include, but are not limited to,include, but are not limited to, ulixertinib, SCH772984, LY3214996,ravoxertinib, VX-11e, and pharmaceutically acceptable salts thereof.Exemplary RAF inhibitors include, but are not limited to, LY3009120,LXH254, RAF709, dabrafenib, vemurafenib, and pharmaceutically acceptablesalts thereof. Exemplary Ras inhibitors include, but are not limited to,AMG-510, MRTX849, and pharmaceutically acceptable salts thereof.

The compounds described herein may be administered in combination withother therapeutic agents known to treat cancers. Such other therapeuticagents include radiation therapy, anti-tubulin agents, DNA alkylatingagents, DNA synthesis-inhibiting agents, DNA intercalating agents,anti-estrogen agents, anti-androgens, steroids, anti-EGFR agents, kinaseinhibitors, mTOR inhibitors, PI3 kinase inhibitors, cyclin-dependentkinase inhibitors, CD4/CD6 kinase inhibitors, topoisomerase inhibitors,Histone Deacetylase (HDAC) inhibitors, DNA methylation inhibitors,anti-HER2 agents, anti-angiogenic agents, proteasome inhibitors, PARPinhibitors, cell cycle regulating kinase inhibitors, thalidomide,lenalidomide, antibody-drug-conjugates (ADCs), immunotherapeutic agentsincluding immunomodulating agents, targeted therapeutic agents, cancervaccines, and CAR-T cell therapy.

In an embodiment, the additional therapeutic agents can bechemotherapeutic agents including but not limited to an anti-tubulinagents (for example, paclitaxel, paclitaxel protein-bound particles forinjectable suspension including nab-paclitaxel, eribulin, docetaxel,ixabepilone, vincristine, auristatins, or maytansinoids), vinorelbine,DNA-alkylating agents (including cisplatin, carboplatin, oxaliplatin,cyclophosphamide, ifosfamide, temozolomide), DNA intercalating agents orDNA topoisomerase inhibitors (including anthracyclines such asdoxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin,mitoxantrone, or epirubicin, camptothecins such as topotecan,irinotecan, or exatecan), 5-fluorouracil, capecitabine, cytarabine,decitabine, 5-aza cytadine, gemcitabine and methotrexate.

In some embodiments, the additional therapeutic agents can be kinaseinhibitors including but not limited to erlotinib, gefitinib, neratinib,afatinib, osimertinib, lapatanib, crizotinib, brigatinib, ceritinib,alectinib, lorlatinib, everolimus, temsirolimus, abemaciclib, LEE011,palbociclib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib,sunitinib, axitinib, dasatinib, imatinib, nilotinib, idelalisib,ibrutinib, BLU-667, Loxo 292, larotrectinib, and quizartinib,anti-estrogen agents including but not limited to tamoxifen,fulvestrant, anastrozole, letrozole, and exemestane, anti-androgenagents including but not limited to abiraterone acetate, enzalutamide,nilutamide, bicalutamide, flutamide, cyproterone acetate, steroid agentsincluding but not limited to prednisone and dexamethasone, PARPinhibitors including but not limited to neraparib, olaparib,talazoparib, and rucaparib, topoisomerase I inhibitors including but notlimited to irinotecan, camptothecin, exatecan, and topotecan,topoisomerase II inhibitors including but not limited to anthracyclines,etoposide, etoposide phosphate, and mitoxantrone, Histone Deacetylase(HDAC) inhibitors including but not limited to vorinostat, romidepsin,panobinostat, valproic acid, and belinostat, DNA methylation inhibitorsincluding but not limited to DZNep and 5-aza-2′-deoxycytidine,proteasome inhibitors including but not limited to bortezomib andcarfilzomib, thalidomide, lenalidomide, pomalidomide, biological agentsincluding but not limited to trastuzumab, ado-trastuzumab, pertuzumab,cetuximab, panitumumab, ipilimumab, tremelimumab, anti-PD-1 agentsincluding pembrolizumab, nivolumab, pidilizumab, and Cemiplimab,anti-PD-L 1 agents including atezolizumab, avelumab, durvalumab andBMS-936559, anti-angiogenic agents including bevacizumab andaflibercept, and antibody-drug-conjugates (ADCs) including DM1, DM4,MMAE, MMAF, or camptothecin payloads, brentuximab vedotin andtrastuzumab emtansine, radiotherapy, therapeutic vaccines including butnot limited to sipuleucel-T.

In some embodiments, the additional therapeutic agents can beimmunomodulatory agents including but not limited to anti-PD-1 oranti-PDL-1 therapeutics including pembrolizumab, nivolumab,atezolizumab, durvalumab, BMS-936559, or avelumab, anti-TIM3(anti-HAVcr2) therapeutics including but not limited to TSR-022 orMBG453, anti-LAG3 therapeutics including but not limited to relatlimab,LAG525, or TSR-033, anti-4-1BB (anti-CD37, anti-TNFRSF9), CD40 agonisttherapeutics including but not limited to SGN-40, CP-870,893 orR07009789, anti-CD47 therapeutics including but not limited to Hu5F9-G4,anti-CD20 therapeutics, anti-CD38 therapeutics, STING agonists includingbut not limited to ADU-S100, MK-1454, ASA404, or amidobenzimidazoles,anthracyclines including but not limited to doxorubicin ormitoxanthrone, hypomethylating agents including but not limited toazacytidine or decitabine, other immunomodulatory therapeutics includingbut not limited to epidermal growth factor inhibitors, statins,metformin, angiotensin receptor blockers, thalidomide, lenalidomide,pomalidomide, prednisone, or dexamethasone.

In some embodiments, the additional therapeutic agent is selected from aluteinizing hormone-releasing hormone (LHRH) analog, including goserelinand leuprolide.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of selected from the group consisting ofeverolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib,GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107,TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457,MLN8054, PHA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatanib,nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu,nolatrexed, azd2171, batabulin, of atumtunab, zanolimumab, edotecarin,tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab,ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490,cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR₁ KRX-0402,lucanthone, LY 317615, neuradiab, vitespan, Rta 744, Sdx 102,talampanel, atrasentan, Xr 311, romidepsin, ADS-100380, sunitinib,5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin,irinotecan, liposomal doxorubicin, 5′-deoxy-5-fluorouridine,vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244,capecitabine, L-Glutamic acid,N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethyl]benzoyl]-,disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan,tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole,DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen,bevacizumab, IMC-1C11, CHIR-258);3-[5-(methylsulfonylpiperadinemethyl)-indolylj-quinolone, vatalanib,AG-013736, AVE-0005, the acetate salt of [D-Ser(Bu t) 6, Azgly 10](pyro-Glu-His-Trp-Ser-Tyr-D-Ser(Bu 0-Leu-Arg-Pro-Azgly-NH₂ acetate[C₅₉H₈₄N₁₈Oi₄-(C₂H₄O₂)_(x) where x=1 to 2.4], goserelin acetate,leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate,hydroxyprogesterone caproate, megestrol acetate, raloxifene,bicalutamide, flutanide, nilutamide, megestrol acetate, CP-724714;TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody,erbitux, EKB-569, PKI-166, GW-572016, Ionafarnib, BMS-214662,tipifarnib; amifostine, NVP-LAQ824, suberoyl analide hydroxamic acid,valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951,aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, BacillusCalmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan,carboplatin, carmustine, chlorambucil, cisplatin, cladribine,clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin,daunorubicin, diethylstilbestrol, epirubicin, fludarabine,fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac,hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole,lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide,oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer,procarbazine, raltitrexed, rituximab, streptozocin, teniposide,testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine,13-cis-retinoic acid, phenylalanine mustard, uracil mustard,estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosinearabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin,mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat,COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668,EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene,idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,denileukin diftitox, gefitinib, bortezimib, irinotecan, topotecan,doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody)and erbitux, cremophor-free paclitaxel, epithilone B, BMS-247550,BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene, ERA-923,arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424,HMR-3339, ZK186619, PTK787/ZK 222584, VX-745, PD 184352, rapamycin,40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,erythropoietin, granulocyte colony-stimulating factor, zolendronate,prednisone, cetuximab, granulocyte macrophage colony-stimulating factor,histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylatedinterferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase,lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane,alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2,megestrol, immune globulin, nitrogen mustard, methylprednisolone,ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine,bexarotene, tositumomab, arsenic trioxide, cortisone, editronate,mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase,strontium 89, casopitant, netupitant, an NK-1 receptor antagonists,palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide,lorazepam, alprazolam, haloperidol, droperidol, dronabinol,dexamethasone, methylprednisolone, prochlorperazine, granisetron,ondansetron, dolasetron, tropisetron, sspegfilgrastim, erythropoietin,epoetin alfa and darbepoetin alfa, ipilumumab, vemurafenib, and mixturesthereof.

Pharmaceutical Compositions and Kits

Another aspect of this disclosure provides pharmaceutical compositionscomprising compounds as disclosed herein formulated together with apharmaceutically acceptable carrier. In particular, the presentdisclosure provides pharmaceutical compositions comprising compounds asdisclosed herein formulated together with one or more pharmaceuticallyacceptable carriers. These formulations include those suitable for oral,rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular,intradermal, or intravenous) rectal, vaginal, or aerosol administration,although the most suitable form of administration in any given case willdepend on the degree and severity of the condition being treated and onthe nature of the particular compound being used. For example, disclosedcompositions may be formulated as a unit dose, and/or may be formulatedfor oral or subcutaneous administration.

Exemplary pharmaceutical compositions may be used in the form of apharmaceutical preparation, for example, in solid, semisolid or liquidform, which contains one or more of the compounds described herein, asan active ingredient, in admixture with an organic or inorganic carrieror excipient suitable for external, enteral or parenteral applications.The active ingredient may be compounded, for example, with the usualnon-toxic, pharmaceutically acceptable carriers for tablets, pellets,capsules, suppositories, solutions, emulsions, suspensions, and anyother form suitable for use. The active object compound is included inthe pharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of the disease.

For preparing solid compositions such as tablets, the principal activeingredient may be mixed with a pharmaceutical carrier, e.g.,conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, and other pharmaceutical diluents, e.g., water, toform a solid preformulation composition containing a homogeneous mixtureof a compound provided herein, or a non-toxic pharmaceuticallyacceptable salt thereof. When referring to these preformulationcompositions as homogeneous, it is meant that the active ingredient isdispersed evenly throughout the composition so that the composition maybe readily subdivided into equally effective unit dosage forms such astablets, pills and capsules.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers, such assodium citrate or dicalcium phosphate, and/or any of the following: (1)fillers or extenders, such as starches, lactose, sucrose, glucose,mannitol, and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate;(5) solution retarding agents, such as paraffin; (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, acetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.In the case of capsules, tablets and pills, the compositions may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugars, as well as high molecularweight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the subject compositionmoistened with an inert liquid diluent. Tablets, and other solid dosageforms, such as dragees, capsules, pills and granules, may optionally bescored or prepared with coatings and shells, such as enteric coatingsand other coatings well known in the pharmaceutical-formulating art.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. Liquid dosage forms for oraladministration include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the subject composition, the liquid dosage forms may contain inertdiluents commonly used in the art, such as, for example, water or othersolvents, solubilizing agents and emulsifiers, such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (inparticular, cottonseed, groundnut, corn, germ, olive, castor and sesameoils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, cyclodextrins and mixtures thereof.

Suspensions, in addition to the subject composition, may containsuspending agents as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing a subject composition withone or more suitable non-irritating excipients or carriers comprising,for example, cocoa butter, polyethylene glycol, a suppository wax or asalicylate, and which is solid at room temperature, but liquid at bodytemperature and, therefore, will melt in the body cavity and release theactive agent.

Dosage forms for transdermal administration of a subject compositioninclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, patches and inhalants. The active component may be mixedunder sterile conditions with a pharmaceutically acceptable carrier, andwith any preservatives, buffers, or propellants which may be required.

The ointments, pastes, creams and gels may contain, in addition to asubject composition, excipients, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays may contain, in addition to a subject composition,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of these substances.Sprays may additionally contain customary propellants, such aschlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

Compositions and compounds of the present disclosure may alternativelybe administered by aerosol. This is accomplished by preparing an aqueousaerosol, liposomal preparation or solid particles containing thecompound. A non-aqueous (e.g., fluorocarbon propellant) suspension couldbe used. Sonic nebulizers may be used because they minimize exposing theagent to shear, which may result in degradation of the compoundscontained in the subject compositions. Ordinarily, an aqueous aerosol ismade by formulating an aqueous solution or suspension of a subjectcomposition together with conventional pharmaceutically acceptablecarriers and stabilizers. The carriers and stabilizers vary with therequirements of the particular subject composition, but typicallyinclude non-ionic surfactants (Tweens, Pluronics, or polyethyleneglycol), innocuous proteins like serum albumin, sorbitan esters, oleicacid, lecithin, amino acids such as glycine, buffers, salts, sugars orsugar alcohols. Aerosols generally are prepared from isotonic solutions.

Pharmaceutical compositions of the present disclosure suitable forparenteral administration comprise a subject composition in combinationwith one or more pharmaceutically-acceptable sterile isotonic aqueous ornon-aqueous solutions, dispersions, suspensions or emulsions, or sterilepowders which may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may beemployed in the pharmaceutical compositions provided herein includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate and cyclodextrins. Proper fluidity may be maintained,for example, by the use of coating materials, such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants.

In another aspect, provided are enteral pharmaceutical formulationsincluding a disclosed compound and an enteric material; and apharmaceutically acceptable carrier or excipient thereof. Entericmaterials refer to polymers that are substantially insoluble in theacidic environment of the stomach, and that are predominantly soluble inintestinal fluids at specific pHs. The small intestine is the part ofthe gastrointestinal tract (gut) between the stomach and the largeintestine, and includes the duodenum, jejunum, and ileum. The pH of theduodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH ofthe distal ileum is about 7.5.

Accordingly, enteric materials are not soluble, for example, until a pHof about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, ofabout 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, ofabout 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, ofabout 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, ofabout 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or ofabout 10.0. Exemplary enteric materials include cellulose acetatephthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP),polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcelluloseacetate succinate (HPMCAS), cellulose acetate trimellitate,hydroxypropyl methylcellulose succinate, cellulose acetate succinate,cellulose acetate hexahydrophthalate, cellulose propionate phthalate,cellulose acetate maleate, cellulose acetate butyrate, cellulose acetatepropionate, copolymer of methylmethacrylic acid and methyl methacrylate,copolymer of methyl acrylate, methylmethacrylate and methacrylic acid,copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series),ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethylacrylate copolymer, natural resins such as zein, shellac and copalcollophorium, and several commercially available enteric dispersionsystems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, EudragitS100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). Thesolubility of each of the above materials is either known or is readilydeterminable in vitro. The foregoing is a list of possible materials,but one of skill in the art with the benefit of the disclosure wouldrecognize that it is not comprehensive and that there are other entericmaterials that would meet the objectives described herein.

Advantageously, provided herein are kits for use by a e.g. a consumer inneed of treatment of cancer. Such kits include a suitable dosage formsuch as those described above and instructions describing the method ofusing such dosage form to mediate, reduce or prevent inflammation. Theinstructions would direct the consumer or medical personnel toadminister the dosage form according to administration modes known tothose skilled in the art. Such kits could advantageously be packaged andsold in single or multiple kit units. An example of such a kit is aso-called blister pack. Blister packs are well known in the packagingindustry and are being widely used for the packaging of pharmaceuticalunit dosage forms (tablets, capsules, and the like). Blister packsgenerally consist of a sheet of relatively stiff material covered with afoil of a preferably transparent plastic material. During the packagingprocess recesses are formed in the plastic foil. The recesses have thesize and shape of the tablets or capsules to be packed. Next, thetablets or capsules are placed in the recesses and the sheet ofrelatively stiff material is sealed against the plastic foil at the faceof the foil which is opposite from the direction in which the recesseswere formed. As a result, the tablets or capsules are sealed in therecesses between the plastic foil and the sheet. Preferably the strengthof the sheet is such that the tablets or capsules can be removed fromthe blister pack by manually applying pressure on the recesses wherebyan opening is formed in the sheet at the place of the recess. The tabletor capsule can then be removed via said opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of a first compound can consistof one tablet or capsule while a daily dose of the second compound canconsist of several tablets or capsules and vice versa. The memory aidshould reflect this.

EXAMPLES

The compounds described herein can be prepared in a number of ways basedon the teachings contained herein and synthetic procedures known in theart. In the description of the synthetic methods described below, it isto be understood that all proposed reaction conditions, including choiceof solvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, can be chosen to be the conditionsstandard for that reaction, unless otherwise indicated. It is understoodby one skilled in the art of organic synthesis that the functionalitypresent on various portions of the molecule should be compatible withthe reagents and reactions proposed. Substituents not compatible withthe reaction conditions will be apparent to one skilled in the art, andalternate methods are therefore indicated. The starting materials forthe examples are either commercially available or are readily preparedby standard methods from known materials.

The following abbreviation are used in this disclosure and have thefollowing definitions: “ADP” is adenosine diphosphate, “Boc” ist-butylcarbonate, “CDI” is carbodiimidazole, “conc.” is concentrated,“Cs₂CO₃” is cesium carbonate, “CuI” is copper (I) iodide, “DBU” is1,8-diazabicyclo[5.4.0]undec-7-ene, “DCC” isN,N′-Dicyclohexylcarbodiimide, “DCE” is dichloroethane, “DCM” isdichloromethane, “DIEA” is N,N-diisopropylethylamine, “DMA” isN,N-dimethylacetamide, “DMAP” is 4-(dimethylamino)pyridine, “DMF” isN,N-dimethylformamide, “dppf” is 1,1′-bis(diphenylphosphino)ferrocene,“DMEM” is Dulbecco's Modified Eagle Media, “DMSO” is dimethylsulfoxide,“DPPA” is diphenylphosphryl azide, “EDC” is1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, “ESI” is electrosprayionization, “Et₂O” is diethylether, “EtOAc” is ethyl acetate, “EtOH” isethanol, “GST” is glutathione S-transferase, “h” is hour or hours,“HBTU” is (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate, “H₂” is hydrogen gas, “HCl” is hydrochloric acid,“Hex” is hexane, “H₂O” is water, “HOBt” is Hydroxybenzotriazole “IC₅₀”is half maximal inhibitory concentration, “K₂CO₃” is potassiumcarbonate, “K₃PO₄” is potassium phosphate, “LiMHDS” is lithiumbis(trimethylsilyl)amide, “MeCN” is acetonitrile, “MeOH” is methanol,“Me₄tBuXPhos” isdi-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine,“MgSO₄” is magnesium sulfate, “MHz” is megahertz, “min” is minute orminutes, “MS” is mass spectrometry, “MTBE” is methyl tert-butyl ether,“NADH” is nicotinamide adenine dinucleotide, “NaH” is sodium hydride,“NaHCO₃” is sodium bicarbonate, “Na₂SO₄” is sodium sulfate, “NH₄Cl” isammonium chloride, “NaSMe” is sodium thiomethoxide, “NBS” isN-bromosuccinimide, “NMR” is nuclear magnetic resonance, “PBS” isphosphate buffered saline, “Pd/C” is palladium on carbon, “Pd₂(dba)₃” istris(dibenzylideneacetone)dipalladium(0), “Pd(OAc)₂” is palladium (II)acetate, “Pd(PPh₃)₄” is tetrakis(triphenylphosphine)palladium (0),“prep-HPLC” is preparative high performance liquid chromatography,“PyBOP” is benzotriazol-1-yl-oxytripyrrolidinophosphoniumhexafluorophosphate, “rt” is room temperature which is also known as“ambient temp,” which will be understood to consist of a range of normallaboratory temperatures ranging from 15-25° C., “satd.” is saturated,“T₃P” is n-propanephosphonic acid anhydride, “TEA” is triethylamine,“TFA” is trifluoroacetic acid, “THF” is tetrahydrofuran, “TMS” istrimethylsilyl, “Tris” is tris(hydroxymethyl)aminomethane, “Xantphos” is4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, “X-Phos” is2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl and “ZnCl₂” iszinc chloride.

General Chemistry

Exemplary compounds described herein are available by the generalsynthetic methods illustrated in the Schemes below, Intermediatepreparations, and the accompanying Examples.

Synthetic Schemes

Scheme 1 illustrates an exemplary preparation of amines D-I-i, D-I-ii,and D-I-iii. Treatment of A-I with amine R⁴—H, which can be aliphatic orheterocyclic, in the presence of a base (e.g. Cs₂CO₃ or K₂CO₃) affordscompound B—I. Further treatment of B—I where R^(2a) is Br withcommercially available boronic esters/boronic acids/trifluoroborates inthe presence of a palladium catalyst (Suzuki coupling) or Sonogashiracoupling reaction affords compound C—I. Intermediate C—I may beselectively converted to amine D-I-i where R^(2b) is alkenyl, alkynyl,or cycloalkyl by mild reducing conditions for example, zinc or ironmetal with ammonium chloride. Intermediate C—I can be fully reduced toD-I-iii by palladium catalyzed hydrogenation. Intermediate B—I whereR^(2a) is Cl, Br, alkyl, CN or alkoxy may be reduced to D-I-ii by mildreducing conditions for example, zinc or iron metal with ammoniumchloride.

In Scheme 1, examples of X include N and CH, examples of Y include N,CH, and C—F where X and Y are not both N, examples of R² include alkyland cycloalkyl, and examples of R⁴ include an N-linked alkyl andN-linked heterocylcyl with suitable optional substituents as exemplifiedby the tables of intermediates below.

Scheme 2 illustrates an exemplary preparation of amine D-II-i, D-II-iiand D-II-iii. Reaction of A-II (commercially available startingmaterials) and amine R⁴—H under reductive amination conditions (e.g.sodium cyanoborohydride or sodium triacetoxyborohydride in the presenceof a catalytic amount of acetic acid in polar solvents like MeOH)affords compound B-II. Further treatment of B-II where R^(2a) is Br withcommercially available boronic esters/boronic acids/trifluoroborates inthe presence of a palladium catalyst (Suzuki coupling) or Sonogashiracoupling reaction affords compound C-II. Intermediate C-II may beselectively converted to amine D-II-i where R^(2b) is alkenyl, alkynyl,cycloalkyl by mild reducing conditions for example, zinc or iron metalwith ammonium chloride. Intermediate C-II can be fully reduced toD-II-iii by palladium catalyzed hydrogenation. Intermediate B-II whereR^(2a) is Cl, Br, alkyl, CN or alkoxy may be reduced to D-II-ii by mildreducing conditions for example, zinc or iron metal with ammoniumchloride.

In Scheme 2, examples of X include N and CH, examples of Y include N,CH, and C—F where X and Y are not both N, examples of R¹ include alkyland cycloalkyl, and examples of R⁴ include an N-linked alkyl andN-linked heterocylcyl with suitable optional substituents as exemplifiedby the tables of interemediates below.

Scheme 3 illustrates an exemplary preparation of amine D-III-i, D-III-iiand D-III-iii. Reduction of A-III-i with reducing reagents such as DIBALaffords aldehyde A-III-ii. Another way to prepare A-III-ii is reductionof A-III-i to the corresponding alcohol followed by mild oxidationconditions such as using MnO₂. Reaction of A-III-ii and amine R⁴—H underreductive amination conditions (e.g. sodium cyanoborohydride or sodiumtriacetoxyborohydride in the presence of a catalytic amount of aceticacid in polar solvents like MeOH) affords compound B-III Another way toprepare B-III is reduction of to the alcohol followed by conversion ofthe alcohol to the sulfonates A-III-iii. Reaction of A-III-iii withamine R⁴—H in the presence of base such as triethylamine, Hunig's base,or cesium carbonate affords B-III Further treatment of B-III whereR^(2a) is Br with commercially available boronic esters/boronicacids/trifluoroborates in the presence of a palladium catalyst (Suzukicoupling) or Sonogashira coupling reaction affords compound C-III.Intermediate C-III may be selectively converted to amine D-III-iii whereR^(2b) is alkenyl, alkynyl, or cycloalkyl by mild reducing conditionsfor example, zinc or iron metal with ammonium chloride. IntermediateC-III can be fully reduced to D-III-ii by palladium catalyzedhydrogenation. Intermediate B-III where R^(2a) is Cl, Br, alkyl, CN oralkoxy may be reduced to D-III-i by mild reducing conditions forexample, zinc or iron metal with ammonium chloride.

In Scheme 3, examples of X include N and CH, examples of Y include N,CH, and C—F where X and Y are not both N, examples of R include methyland ethyl, examples of R² include alkyl and cycloalkyl, examples of R⁴include an N-linked alkyl and N-linked heterocylcyl with suitableoptional substituents as exemplified by the tables of interemediatesbelow, and examples of LG include mesylate and tosylate.

Scheme 4 illustrates an exemplary preparation of amine D-IV. Reaction ofA-III-i and various amines under amide coupling reagents (e.g. CDI, DCC,EDC, HOBt, HBTU, PyBOP, or T₃P) in the presence of a catalytic amount ofDMAP, if needed, affords amide B-IV. Further treatment of B-IV whereR^(2a) is Br with commercially available boronic esters/boronicacids/trifluoroborates in the presence of a palladium catalyst (Suzukicoupling) or Sonogashira coupling reaction affords compound C-IV.Intermediate C-IV may be selectively converted to amine D-IV-i whereR^(2b) is alkenyl, alkynyl, or cycloalkyl by mild reducing conditionsfor example, zinc or iron metal with ammonium chloride. IntermediateC-IV can be fully reduced to D-IV-iii by palladium catalyzedhydrogenation. Intermediate B-IV where R^(2a) is Cl, Br, alkyl, CN oralkoxy may be reduced to D-IV-ii by mild reducing conditions forexample, zinc or iron metal with ammonium chloride.

In Scheme 4, examples of X include N and CH, examples of Y include N,CH, and C—F where X and Y are not both N, examples of R include methyland ethyl, examples of R² include alkyl and cycloalkyl, and examples ofR⁴ include —C(O)-alkyl and —C(O)-heterocylcyl, where the alkyl andheterocyclyl moieties are N-linked with suitable optional substituentsas exemplified by the tables of interemediates below.

Scheme 5 illustrates an exemplary preparation of amine D-V. B-V reactswith boronic esters/boronic acids/trifluoroborates in the presence of apalladium catalyst (Suzuki coupling) to afford compound C-V. Manyboronic esters/boronic acids/trifluoroborates are commercially availableand those that are not can be readily prepared from the correspondingcarboxylic acids (see Scheme 7). Intermediate C-V may be converted toamine D-V by standard reducing conditions, for example, by palladiumcatalyzed hydrogenation or by mild reducing conditions including zincmetal and ammonium chloride.

In Scheme 5, examples of X include N and CH, examples of Y include N,CH, and C-F, examples of R² include alkyl and cycloalkyl, and examplesof R⁴ include a C-linked heterocylcyl and heteroaryl with suitableoptional substituents as exemplified by the tables of interemediatesbelow.

Scheme 6 illustrates an exemplary preparation of D-VI from C-VI-i where,in C-VI-i, R⁴ contains a nitrogen protecting group, e.g. a Boc group.C-VI-i can be deprotected under acidic conditions to provide the aminesalt. Further treatment of the salt with sodium cyanoborohydride orsodium triacetoxyborohydride and an aldehyde or ketone in the presenceof a catalytic amount of acetic acid in polar solvents such as MeOH(reductive amination conditions) affords C-VI. Intermediate C-VI may beconverted to aniline D-VI by standard reducing conditions, for example,by palladium catalyzed hydrogenation or by mild reducing conditionsincluding zinc metal and ammonium chloride.

In Scheme 6, examples of X include N and CH, examples of Y include N,CH, and C—F where X and Y are not both N, examples of R² include alkyland cycloalkyl, and examples of R⁴ include heterocylcyl with suitableoptional substituents as exemplified by the tables of interemediatesbelow.

Scheme 7 illustrates an exemplary preparation of boronic acid/boronicester T, which are not commercially available. These compounds can bereadily prepared from the substituted carboxylic acid. The startingmaterial carboxylic acid can be activated by2-hydroxyisoindoline-1,3-dione in the presence of coupling reagent (e.g.DCI or Et₃N/HATU) to afford Q. Intermediate Q may be converted toboronic ester T by nickel-catalyzed decarboxylation borylation with the[B₂pin₂Me]Li complex, which is premixed with methyllithium and B₂pin₂(Science, 356, 1045 (2017), JACS, 138, 2174 (2016)).

In Scheme 7, examples of m include 0, 1, and 2, and examples of R⁴include alkyl, cycloalkyl, and heterocyclyl with suitable optionalsubstituents as exemplified by the tables of interemediates below.

Scheme 8 illustrates an exemplary preparation of L-I-1 and L-I-2.Commercially available 2,4-dichloro-5-iodopyrimidine reacts with TMSCF2Hin a solvent such as NMP or DMF in the presence of CuI and CsF toproduce difluoromethylpyrimidine L-II-1 (US20150284341).Difluoromethylpyrimidine L-II-1 can be converted tothiomethyletherpyrimidine L-I-1 by treatment with sodium thiomethoxideand zinc chloride in diethyl ether at temperatures lower than 10° C.(WO2012110773). In a similar manner to L-I-1, trifluoromethylpyrimidineL-I-2 can be prepared from the commercially available2,4-dichloro-5-(trifluoromethyl)pyrimidine, L-II-2.

Scheme 9 illustrates an exemplary preparation of sulfonylpyrimidineL-III (t=2) where R¹ can be cycloalkyl. Treatment of commerciallyavailable 5-bromo-2-chloro-4-(methylthio)pyrimidine with commerciallyavailable boronic esters/boronic acids/trifluoroborates (see scheme 7)in the presence of a palladium catalyst (Suzuki coupling) affordsthiopyrimidine L-III (t=0). The intermediate thiopyrimidine L-III (t=0)may be converted to sulfonylpyrimidine L-III (t=2) by standardoxidations, for example, by mCPBA.

Scheme 10 illustrates an exemplary preparation of intermediate H(I-XIII) using a widely known method. Treatment of commerciallyavailable lactam/cyclic-carbamate/oxolactam/cyclic-urea/diazepanone Ewith (Boc)-protected bromo-intermediate F in the presence of base, forexample sodium hydride or potassium tert-butoxide, provides G. The Bocprotecting group of G may be removed upon exposure to acid, for exampleHCl or TFA.

In Scheme 10, q can be 0, 1, 2, or 3, r can be 2, 3, or 4, V can beC(R³⁴)₂, O, or NR⁶, where R⁶ is alkyl, n can be 2, 3, or 4, each R³⁴can, independently, be H, C₁-C₆alkyl, or two R³⁴ can be taken togetherto form a cycloalkyl.

In another embodiment to prepare H, H-XIV can be prepared from DBU viaone step process as illustrated in Scheme 11. DBU can be hydrolyzed bypotassium hydroxide in the solution of methanol and water at ambienttemperature to provide H-XIV.

Scheme 12 illustrates an exemplary preparation of key intermediates Jand K. Key intermediate J can be prepared from H (either free base oracid addition salt) by reacting with thiopyrimidine L-I in the presenceof an organic base (e. g. triethylamine or DIEA) and optional heating.In a similar manner, key intermediate K can be prepared from H witheither L-II or L-III

In Scheme 12, q can be 0, 1, 2, or 3, r can be 2, 3, or 4, V can beC(R³⁴)₂, O, or NR⁶, where R⁶ is alkyl, n can be 2, 3, or 4, each R³⁴can, independently, be H, C₁-C₆alkyl, or two R³⁴ can be taken togetherto form a cycloalkyl group.

Scheme 13 illustrates an exemplary preparation of key intermediate M.Treatment of H with commercially available iodopyridine underBuchwald-Hartwig coupling conditions (Cs₂CO₃, Xantphos and Pd(OAc)₂),typically performed in an aprotic solvent (e.g. DME, DME, DMSO, or NMP)at temperatures ranging from ambient temp to 140° C., provides keyintermediate M.

In Scheme 13, R¹ can be Br, Cl, alkyl optionally substituted by one ormore fluorine atoms, or cycloalkyl, q can be 0, 1, 2, or 3, r can be 2,3, or 4, V can be C(R³⁴)₂, O, or NR⁶, where R⁶ is alkyl, n can be 2, 3,or 4, each R³⁴ can, independently, be H, C₁-C₆alkyl, or two R³⁴ can betaken together to form a cycloalkyl.

Scheme 14 illustrates an exemplary preparation of compounds of Formula Ifrom substituted anilines or aminopyridines (D-I). The preparation ofFormula I-A can be accomplished from key intermediates K and J. First, anucleophilic substitution reaction of K with amine D can be typicallyperformed in an aprotic solvent at temperatures ranging from ambienttemp to 150° C., in some embodiments with microwave heating, optionallyin the presence of an acid for example 4 N HCl in 1,4-dioxane to provideFormula I-A. Compounds D-I, which are not commercially available, can bereadily prepared from substituted nitrobenzenes or nitropyridines (seeschemes 1-6). An alternative general synthesis of Formula I-A is via atwo-step process by first converting J(t=0) to sulfoxide (J(t=1, majorproduct) by oxidation using various oxidants, for example mCPBA. Thesulfoxide reacts with amine D-I by a nucleophilic substitution reaction,typically performed in an aprotic solvent at temperatures ranging fromambient temp to 150° C., in some embodiments with microwave heating,optionally in the presence of an acid for example 4 N HCl in 1,4-dioxaneor pTSA. Formula I-A which contains a nitrogen protecting group such asa Boc group, can be deprotected under acidic conditions to provideFormula I-A containing a free NH on R⁴ (free amine or acid additionsalt). Further treatment of Formula I-A (free base or acid additionsalt) with sodium cyanoborohydride or sodium triacetoxyborohydride andan aldehyde or ketone in the presence of a catalytic amount of aceticacid in polar solvents such as MeOH (reductive amination conditions)affords R⁴ N-substituted Formula I-A. For acylation and sulfonylation,the free amine (or salt) can be treated with commercially available acylchloride or sulfonyl chloride to afford N-substituted Formula I-A.

Scheme 15 illustrates exemplary preparations of compounds of FormulaI-B. The preparation of Formula I-B can be accomplished byBuchwald-Hartwig coupling reaction with D-I and M. Amines D-I which arenot commercially available can be readily prepared from substitutednitrobenzene or nitropyridine (see schemes 1-6). Formula I-B whichcontains a nitrogen protecting group such as a Boc group can bedeprotected under an acidic condition to provide Formula I-B containinga free NH on R⁴ (free amine or acid addition salt). Further treatment ofFormula I-B (free base or acid addition salt) with sodiumcyanoborohydride or sodium triacetoxyborohydride and an aldehyde orketone in the presence of a catalytic amount of acetic acid in polarsolvents such as MeOH (reductive amination conditions) affords R⁴N-substituted Formula I-B. In a same manner as Scheme 14, the free amine(or acid addition salt) can be treated with commercially available acylchloride or sulfonyl chloride to afford N-substituted Formula I-B.

PREPARATION OF INTERMEDIATES

Using the synthetic procedures and methods described herein and methodsknown to those skilled in the art, the following compounds were made:

General Method A: Aromatic Nucleophilic Substitution Intermediate B-I-8:1-(3-bromo-4-nitrophenyl)-4-methylpiperazine

A mixture of 2-bromo-4-fluoro-1-nitrobenzene (50 g, 227 mmol) and1-methylpiperazine (24 g, 250 mmol) in DMF (400 mL) was treated withK₂CO₃ (63 g, 455 mmol) at RT and the reaction mixture was stirred at 60°C. for 16 h. The reaction mixture was diluted with ice water (500 mL)and the precipitated solid was filtered. The solid was furthertriturated with Et₂O and n-pentane to obtained1-(3-bromo-4-nitrophenyl)-4-methylpiperazine (58 g, 85% yield) as ayellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 7.98 (d, J=9.4 Hz, 1H), 7.24(d, J=2.1 Hz, 1H), 7.01 (dd, J=2.2 and 9.4 Hz, 1H), 3.42 (m, 4H), 2.40(m, 4H), 2.19 (s, 3H); LC-MS (ESI) m/z: 299.0 (M+H⁺).

General Method B: Deprotection and Reductive Amination IntermediateB-I-24: 3-(3-bromo-4-nitrophenyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane

A solution of tert-butyl3-(3-bromo-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(B-I-14, 2.57 g, 6.2 mol) in MeOH (30 mL) was treated with 4 N HCl in1,4-dioxanes (16 mL, 62 mmol) and the reaction mixture was stirred at rt16 h. The reaction mixture was concentrated to dryness under vacuum toprovide 3-(3-bromo-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octanehydrochloride (2.17 g, 100% yield) as a white solid. Material wascarried forward without further purification. A suspension of3-(3-bromo-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane hydrochloride(1.92 g, 5.5 mmol) in DCE (25 mL) was treated with DIEA (2.9 mL, 17mmol) and formaldehyde (1.2 mL, 17 mmol). The yellow suspension became aclear orange solution. The reaction mixture was stirred for 10 min at rtand then acetic acid (0.63 mL, 11 mmol) was added. The orange solutionbecame a yellow suspension which was stirred for 20 min. Sodiumtriacetoxyborohydride (2.33 g, 11 mmol) was added and the reactionmixture was stirred at rt for 4 h. The reaction mixture was diluted withaqueous NaHCO₃ (50 mL) and the solution was extracted with DCM (3×50mL). The combined organics were dried over anhydrous Na₂SO₄, filtered,and concentrated to afford a brown solid. The brown solid was purifiedusing silica gel column chromatography (0 to 15% MeOH/DCM) to afford3-(3-bromo-4-nitrophenyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane (1.71g, 95% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6): δ 7.98 (d,J=9.4 Hz, 1H), 7.10 (d, J=2.7 Hz, 1H), 6.89 (dd, J=9.5 and 2.7 Hz, 1H),3.54 (d, J=11.6 Hz, 2H), 3.22 (brs, 2H), 2.99-3.04 (m, 2H), 2.22 (s,3H), 1.92-1.95 (m, 2H), 1.52-1.56 (m, 2H); LC-MS (ESI) m/z: 326.0(M+H⁺).

General Method C: Alkylation Intermediate B-I-23:1-(2-fluoroethyl)-4-(3-methyl-4-nitrophenyl)piperazine

A mixture of 1-(3-methyl-4-nitrophenyl)piperazine hydrochloride(Boc-deprotected product of B-I-3 1.5 g, 0.58 mmol) and K₂CO₃ (4.0 g,2.9 mmol) in 1,4-dioxane (20 mL) was treated with 1-fluoro-2-iodoethane(2.0 mL, 2.6 mmol) [Note: material described as prone toinstability—some solids present in the orange liquid], capped tightlyand heated to 100° C. for 24 h. The mixture was cooled to rt and thesolids (K₂CO₃) were removed via filtration, rinsed with DCM and thefiltrate was concentrated to dryness to afford1-(2-fluoroethyl)-4-(3-methyl-4-nitrophenyl)piperazine (1.52 g, 98%yield) as a yellow oil which solidified upon standing to an amber solid.¹H NMR (400 MHz, DMSO-d₆): δ 7.97 (d, J=9.6 Hz, 1H), 6.87-6.89 (m, 2H),4.61 (t, J=4.9 Hz, 1H), 4.52 (t, J=4.9 Hz, 1H), 3.41 (m, 4H), 2.69 (t,J=4.9 Hz, 1H), 2.63 (t, J=4.9 Hz, 1H), 2.54-2.56 (m, 7H); LC-MS (ESI)m/z: 268.2 (M+H⁺).

Using the General Methods A-C above, the following Intermediates inTable A were prepared.

TABLE A Yield ¹H NMR (400 MHz, LC-MS Intermediate Structure Method (%)DMSO-d₆): δ (m/z: (M + H⁺) B-I-1

A 90 8.04 (d, J = 9.4 Hz, 2H), 7.02 (d, J = 9.4 Hz, 2H), 3.44 (brs, 4H),2.41 (brs, 4H), 2.21 (s, 3H). 222.1 B-I-2

A 81 8.03 (d, 2H), 7.01 (d, 2H), 3.40 (t, J = 5.0 Hz, 4H), 2.63 (t, J =5.0 Hz, 4H), 1.63-1.67 (m, 1H), 0.42-0.45 (m, 2H), 0.33-0.36 (m, 2H).248.2 B-I-3

A 96 7.99 (d, J = 9.0 Hz, 1H), 6.86- 6.88 (m, 2H), 3.43 (s, 8H), 2.54(s, 3H), 1.41 (s, 9H). 322.2 B-I-4

A 90 7.97 (d, J = 9.6 Hz, 1H), 6.87 (m, 2H), 3.37 (brs, 4H), 2.62 (brs,4H), 2.54 (s, 3H), 1.64 (m, 1H), 0.43 (m, 2H), 0.36 (m, 2H). 262.3 B-I-5

A 87 7.99 (d, J = 9.2 Hz, 1H), 6.58 (brs, 2H), 4.82 (s, 1H), 4.69 (s,1H), 3.78 (m, 1H), 3.63 (m, 1H), 3.52 (m, 1H), 3.16 (d, J = 10.0 Hz,1H), 2.54 (s, 3H), 1.91 (m, 2H). 235.1 B-I-6

A 80 No NMR Data 322.2 B-I-7

A 54 7.95-7.98 (m, 1H), 6.72-6.74 (m, 2H), 3.73 (t, J = 6.0 Hz, 1H),3.68 (t, J = 5.6 Hz, 1H), 3.58-3.62 (m, 2H), 3.54 (t, J = 6.0 Hz, 1H),3.47 (t, J = 5.6 Hz, 1H), 3.26 (t, J = 5.2 Hz, 1H), 3.19 (t, J = 5.7 Hz,1H), 2.54 (d, J = 3.3 Hz, 3H), 1.80 (t, J = 6.3 Hz, 1H), 1.73 (s, 1H),1.28 (s, 4H), 1.14 (s, 5H). 358.2 (M + Na + H⁺) B-I-9

A 100 8.01 (d, J = 9.3 Hz, 1H), 7.24 (m, 1H), 7.01 (m, 1H), 3.44 (brs,8H), 1.41 (s, 9H). 408.0 410.0 (M + Na + H⁺) (M + Na + 3H⁺) B-I-10

B 92 7.98 (d, J = 9.4 Hz, 1H), 7.24 (d, J = 2.7 Hz, 1H), 7.01 (dd, J =9.4 and 2.7 Hz, 1H), 3.42 (t, J = 5.0 Hz, 4H), 2.44 (t, J = 5.0 Hz, 4H),2.35 (q, J = 7.2 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H). No data B-I-11

B 95 No NMR Data 328.0 330.0 B-I-12

A 58 8.02 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.05 (dd, J =8.0 and 2.0 Hz, 1H), 3.73 (m, 2H), 3.41 (m, 2H). 287.0 289.0 B-I-13

A 53 8.0 (d, J = 9.2 Hz, 1H), 7.24 (s, 1H), 6.99 (m, 1H), 4.02 (s, 2H),3.72 (brs, 2H), 3.45 (d, J = 4.0, 2H), 2.90 (s, 3H). 313.0 315.0 B-I-14

A 76 7.99 (d, J = 9.5 Hz, 1H), 7.19 (s, 1H), 6.95-6.97 (m, 1H),4.16-4.23 (m, 2H), 3.72 (d, J = 12.1Hz, 2H), 2.99 (d, J = 12.1 Hz, 2H),1.85 (brs, 2H), 1.67 (d, J = 7.5 Hz, 2H), 1.41 (s, 9H). No Data B-I-15

A 37 7.99 (d, J = 9.4 Hz, 1H), 7.18 (d, J = 2.7 Hz, 1H), 6.96 (dd, J =9.4 and 2.8 Hz, 1H), 4.57 (t, J = 4.2 Hz, 1H), 3.44 (dd, J = 12.9 and5.6 Hz, 1H), 3.01-3.07 (m, 1H), 2.88-2.97 (m, 3H), 2.80-2.86 (m, 1H),2.71 (dd, J = 13.3, 4.9 Hz, 1H), 2.51 (s, 1H), 1.85-1.92 (m, 1H),1.69-1.75 (m, 1H). No Data B-I-16

A 87 8.02 (m, 1H), 7.33 (m, 1H), 3.26 (m, 4 H), 2.43 (m, 4 H), 2.20 (s,3 H). 318.0 320.0 B-I-17

A 20 8.03 (d, J = 9.2 Hz, 1H), 6.93 (s, 1H), 6.69 (d, J = 9.3 Hz, 1H),3.72 (t, J = 8.5 Hz, 1H), 3.58-3.66 (m, 2H), 3.52 (t, J = 7.8 Hz, 1H),3.41-3.46 (m, 1H), 2.35-2.42 (m, 1H), 2.23- 2.30 (m, 1H). No Data B-I-18

A 76 8.03 (d, J = 9.2 Hz, 1H), 6.93 (d, J = 2.6 Hz, 1H), 6.68 (dd, J =9.3, 2.6 Hz, 1H), 3.70- 3.73 (m, 1H), 3.58-3.66 (m, 2H), 3.53 (dt, J =10.3 and 6.8 Hz, 1H), 3.41-3.46 (m, 1H), 2.36-2.41 (m, 1H), 2.23-2.30(m, 1H). No Data B-I-19

A 77 7.97 (dd, J = 9.4 and 4.1 Hz, 1H), 7.07 (s, 1H), 6.86 (d, J = 9.6Hz, 1H), 3.47-3.76 (m, 6 H), 3.21-3.28 (m, 2H), 1.67- 1.81 (m, 2H), 1.21(s, 9H). 422.2 424.2 B-I-20

A 36 7.98 (d, J = 9.4 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.03 (dd, J =9.4, 2.8 Hz, 1H), 4.11 (d, J = 12.2 Hz, 1H), 3.95 (d, J = 12.7 Hz, 1H),2.92-3.05 (m, 3H), 2.63 (t, J = 11.3 Hz, 1H), 2.15 (t, J = 11.3 Hz, 1H),2.06 (q, J = 8.7 Hz, 1H), 1.91-2.00 (m, 1H), 1.80-1.86 (m, 1H),1.64-1.73 (m, 2H), 1.30-1.40 (m, 1H). 326.0 328.0 B-I-21

A 64 7.98 (d, J = 9.4 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.03 (dd, J =9.4, 2.8 Hz, 1H), 4.11 (d, J = 12.2 Hz, 1H), 3.95 (d, J = 12.7 Hz, 1H),2.92-3.05 (m, 3H), 2.63 (t, J = 11.3 Hz, 1H), 2.15 (t, J = 11.3 Hz, 1H),2.06 (q, J = 8.7 Hz, 1H), 1.91-2.00 (m, 1H), 1.80-1.86 (m, 1H),1.64-1.73 (m, 2H), 1.30-1.40 (m, 1H). 326.0 328.0 B-I-22

A 86 7.97 (d, J = 9.6 Hz, 1H), 6.88 (d, J = 8.0 Hz, 2H), 3.40 (brs, 4H),2.54 (s, 3H), 2.40 (brs, 4H), 2.20 (s, 3H). 236.2 B-I-25

A 41 8.00 (d, J = 9.1 Hz, 1H), 6.69 (d, J = 2.5 Hz, 1H), 6.44 (dd, J =9.1 and 2.5 Hz, 1H), 4.05 (m, 2H), 3.81 (dd, J = 9.1, 5.1 Hz, 2H), 2.11(s, 6H). 300.2 302.2 B-I-26

B 44 7.99 (d, J = 9.3 Hz, 1H), 6.60- 6.91 (brm, 2H), 4.59 (s, 1H), 3.49(s, 1H), 3.34 (s, 2H), 2.81 (dd, J = 9.6 and 2.0 Hz, 1H), 2.42, (d, J =9.7 Hz, 1H), 2.27 (s, 3H), 1.90 (m, 1H), 1.75 (m, 1H). 312.0 314.0B-I-27

A 90 8.86 (s, 1H), 6.83 (s, 1H), 3.68 (brs, 8H), 2.51 (s, 3H). 224.33B-I-28

A 99 8.84 (s, 1H), 6.83 (s, 1H), 3.71 (brs, 4H), 2.52 (s, 3H), 2.37(brs, 4H), 2.20 (s, 3H). 237.2 B-I-29

A 83 8.84 (s, 1H), 6.79 (s, 1H), 3.71 (brs, 4H), 2.89 (q, 2H), 2.38(brs, 4H), 2.21 (s, 3H), 1.19 (t, J = 7.4 Hz, 3H). 251.2 B-I-30

A 74 7.87 (d, J = 9.2 Hz, 1H), 6.59 (d, J = 9.2 Hz, 1H), 6.53 (s, 1H),3.90 (s, 3H), 3.43 (s, 4H), 2.41 (s, 4H), 2.21 (s, 3H), 252.1 B-I-31

A 71 7.82 (d, J = 9.2 Hz, 1H), 6.51 (m, 2H), 4.82 (m, 1H), 3.92 (m, 4H),2.40 (m, 4H), 2.21 (s, 3H), 1.28 (d, J = 6.0 Hz, 6H). 280.1 B-I-32

B 87 7.99 (d, J = 9.3 Hz, 1H), 6.60- 6.91 (brm, 2H), 4.59 (s, 1H), 3.49(s, 1H), 3.34 (s, 2H), 2.81 (dd, J = 9.6 and 2.0 Hz, 1H), 2.42, (d, J =9.7 Hz, 1H), 2.27 (s, 3H), 1.90 (m, 1H), 1.75 (m, 1H). 312.0 314.0 B-I-A

A 57 7.88 (d, J = 9.1 Hz, 1H), 5.98 (dd, J = 9.1, 2.2 Hz, 1H), 5.80 (d,J = 2.3 Hz, 1H), 4.20 (t, J = 8.3 Hz, 2H), 3.83 (t, J = 7.1 Hz, 2H),3.47 (d, J = 7.2 Hz, 2H), 3.27 (m, 1H), 2.81 (s, 6H). 314.0 316.0 B-I-B

A crude No NMR Data 280.2 B-I-C

A 70 8.01 (d, J = 9.3 Hz, 1H), 6.86 (d, J = 2.6 Hz, 1H), 6.61 (dd, J =2.6 and 9.3 Hz, 1H), 3.54 (m, 1H), 3.44 (m, 1H), 3.35 (m, 1H), 3.12 (m,1H), 2.77 (m, 1H), 2.18 (s, 6H), 2.14 (m, 1H), 1.80 (m, 1H). 314.2 316.2B-I-D

A 58 8.01 (d, J = 9.3 Hz, 1H), 6.86 (d, J = 2.6 Hz, 1H), 6.61 (dd, J =2.6 and 9.3 Hz, 1H), 3.54 (m, 1H), 3.44 (m, 1H), 3.35 (m, 1H), 3.12 (m,1H), 2.77 (m, 1H), 2.18 (s, 6H), 2.14 (m, 1H), 1.80 (m, 1H). 336.2 338.2(Na) B-I-E

A 57 No NMR Data 314.2 B-I-F

A 74 7.99 (d, J = 9.4 Hz, 1H), 7.07 (d, J = 2.7 Hz, 1H), 6.96 (dd, J =2.7 and 9.5 Hz, 1H), 3.42 (t, J = 5.1 Hz, 4H), 2.39 (t, J = 5.1 Hz, 4H),2.20 (s, 3H). 256.0

Intermediate B-I-33: 1-(3-bromo-4-nitrophenyl)-4-methylpiperazin 2-one

A mixture of tert-butyl (2-aminoethyl) (methyl)carbamate (4.3 g, 24mmol) and potassium carbonate (3.8 g, 27 mmol) in DMF (50 mL) wastreated with 4-fluoro-2-bromo-1-nitrobenzene (5 g, 22 mmol) at rt underN₂ atmosphere and the mixture was stirred at 90° C. for 16 h. Thereaction mixture was diluted with water (200 mL) and the solution wasextracted with EtOAc (2×100 mL), The combined organics were dried overanhydrous Na₂SO₄, filtered and concentrated. The crude was purified bysilica gel column chromatography (2% MeOH/DCM, 10 CV's) to givetert-butyl (2-((3-bromo-4-nitrophenyl)amino)ethyl)(methyl)carbamate (5.6g, 66% yield) as a yellow liquid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.98 (d,J=9.0 Hz, 1H), 6.77 (S, 1H), 6.46 (d, J=9.0 Hz, 1H), 3.54 (s, 2H), 3.31(t, J=6.0 Hz, 2H), 2.90 (s, 3H), 1.47 (s, 9H); LC-MS (ESI) m/z: 374.1(M+H⁺).

A mixture of tert-butyl(2-((3-bromo-4-nitrophenyl)amino)ethyl)(methyl)carbamate (5.6 g, 15mmol) and TEA (7.6 g, 75 mmol) in DCM (100 mL) was treated withchloroacetylchloride (5.1 g, 45 mmol) at 0° C. under N₂ atmosphere andthe mixture was stirred at rt for 16 h. The reaction mixture was dilutedwith water (100 mL) and the solution was extracted with DCM (2×100 mL).The combined organics were evaporated under reduced pressure and thecrude was purified by silica gel column chromatography (2% MeOH/DCM, 10CV's) to obtain tert-butyl(2-(N-(3-bromo-4-nitrophenyl)-2-chloroacetamido)ethyl)(methyl)carbamate(5.6 g, 66% yield) as a yellow liquid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.12(d, J=8.6 Hz, 1H), 7.97 (s, 1H), 6.66 (d, J=7.4 Hz, 1H), 4.24 (m, 2H),3.82 (s, 2H), 3.18 (s, 2H), 2.70 (s, 3H), 1.41 (s, 9H); LC-MS (ESI) m/z:374.1 (M+H⁺).

A solution ofN-(3-bromo-4-nitrophenyl)-2-chloro-N-(2-(methylamino)ethyl)acetamidehydrochloride (5.6 g, 12 mmol) in dioxane (100 mL) was treated with 4 NHCl in 1,4-dioxane (100 mL) at 0° C. under N₂ atmosphere and thereaction mixture was stirred at rt for 16 h. The reaction mixtureevaporated under reduced pressure and the crude was purified bycrystallization in Et₂O (100 mL) to obtainN-(3-bromo-4-nitrophenyl)-2-chloro-N-(2-(methylamino)ethyl)acetamidehydrochloride (4.79 g, 99% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.75 (brs, 2H), 8.16 (m, 2H), 7.83 (d, J=7.8 Hz, 1H), 4.20(s, 2H), 3.98 (t, 2H), 3.20 (s, 2H), 2.56 (s, 3H), 1.41 (s, 9H); LC-MS(ESI) m/z: 374.1 (M+H⁺).

A solution ofN-(3-bromo-4-nitrophenyl)-2-chloro-N-(2-(methylamino)ethyl)acetamidehydrochloride (5.0 g, 12 mmol) in DMF (50 mL) was added to NaH in 60%mineral oil (1.1 g, 25 mmol) at 0° C. under N₂ atmosphere and thereaction mixture was stirred at rt for 2 h. The reaction mixture wasdiluted with water (100 mL) and the solution was extracted with EtOAc(2×50 mL), The combined organics were evaporated under reduced pressureand the crude was purified by silica gel column chromatography (2%MeOH/DCM, 10 CV's) to give1-(3-bromo-4-nitrophenyl)-4-methylpiperazin-2-one (3.1 g, 76% yield) asa yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.0 (d, J=9.4 Hz, 1H), 7.24(d, J=2.3 Hz, 1H), 6.99 (dd, J=2.3 and 9.3 Hz, 1H), 4.0 (s, 2H), 3.72(t, J=5.4 Hz, 2H), 3.45 (t, J=5.4 Hz, 2H), 2.90 (s, 3H); LC-MS (ESI)m/z: 314.2 (M+H⁺).

Intermediate B-I-34:1-(3-(methoxymethyl)-4-nitrophenyl)-4-methylpiperazine

A solution of (5-(4-methylpiperazin-1-yl)-2-nitrophenyl)methanol (1.0 g,4.0 mmol) in DMF (30 mL) was cooled to 0° C. Sodium hydride (0.80 g, 60%in mineral) was added in portions and the mixture was stirred under thesame conditions. Iodomethane (1.7 g, 12 mmol) was added at 0° C. and themixture was slowly warmed to rt and stirred for 2 h. The reaction wasdiluted with EtOAc and carefully quenched with ice water. The mixturewas extracted with EtOAc (3×30 mL) and the combined organic extractswere dried over anhydrous Na₂SO₄, filtered and concentrated under thereduced pressure to obtain the crude. The crude was purified by silicagel column chromatography (hexane/EtOAc)1-(3-(methoxymethyl)-4-nitrophenyl)-4-methylpiperazine (0.76 g, 72%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.03 (m, 1H), 7.08 (s, 1H), 6.96(m, 1H), 4.76 (s, 2H), 3.45 (brs, 4H), 3.40 (s, 3H), 2.42 (brs, 4H),2.22 (s, 3H); LC-MS (ESI) m/z: 266.2 (M+H⁺).

General Method D: Suzuki Coupling Reaction Intermediate C-V-4:1-methyl-4-(3-methyl-4-nitrophenyl)-1H-imidazole

A suspension of4,4,5,5-tetramethyl-2-(3-methyl-4-nitrophenyl)-1,3,2-dioxaborolane (0.80g, 3.0 mmol) and 4-bromo-1-methyl-1H-imidazole (0.49 g, 3.0 mmol) in amixture of 1,4-dioxane (12 mL) and water (0.5 mL) was treated withpotassium carbonate (1.26 g, 9.1 mmol) and the suspension was allowed tostir. The reaction mixture was degassed by bubbling argon for twominutes and treated with Pd(dppf)Cl₂.DCM adduct (0.50 g, 0.61 mmol). Theresulting reaction mixture was heated at 100° C. 16 h. The reaction wasdiluted with water and extracted with DCM (4×25 mL). The organics werecombined and dried over anhydrous Na₂SO₄, filtered and concentrated todryness under vacuum to afford a black oil. The black oil was purifiedusing silica gel (0 to 15% MeOH/DCM, 15 CV's) to obtain1-methyl-4-(3-methyl-4-nitrophenyl)-1H-imidazole (0.31 g, 47% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 8.02 (d, J=8.6 Hz, 1H), 7.84 (d, J=7.7 Hz,2H), 7.77 (d, J=8.6 Hz, 1H), 7.72 (s, 1H), 3.70 (s, 3H), 2.57 (s, 3H);LC-MS (ESI) m/z: 218.2 (M+H⁺).

Using the General Method D above, the following Intermediates of Table Bwere prepared.

TABLE B ¹H NMR LC-MS Yield (400 MHz, (m/z: Intermediate Structure Method(%) DMSO-d₆): δ (M + H⁺) C-V-1

D 62 No NMR Data 319.2 C-V-2

D 64 No NMR Data 233.2 C-V-3

D 72 8.34 (s, 1H), 8.02 (s, 1H), 8.00 (s, 1H), 7.72 (s, 1H), 7.63 (m,1H), 3.88 (s, 3H), 2.56 (s, 3H). 218.2

General Method E: Suzuki Coupling Reaction Intermediate C-I-1:1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine

A mixture of 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine (B-I-8, 20 g,67 mmol) and cyclopropylboronic acid (8.6 g, 100 mmol) in toluene: H₂O(9:1) (200 mL) was treated with K₃PO₄ (43 g, 200 mmol) and the reactionmixture was purged with nitrogen for 20 min. Tricyclohexyl phosphine(3.7 g, 13 mmol) and Pd(OAc)₂ (2.2 g, 10 mmol) were added into thereaction mixture and then the reaction mixture was stirred at 100° C.for 5 h. the reaction mixture was diluted with water (100 mL) and thesolution was extracted with EtOAc (3×200 mL). The combined organicextracts were washed with brine (50 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The crude was purified by silica gel columnchromatography (0 to 80% EtOAc/hexane, 15 CV's) to obtain1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine (12 g, 69% yield) asa yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.89 (d, J=9.3 Hz, 1H),6.85 (dd, J=2.4 and 9.4 Hz 1H), 6.55 (s, 1H), 3.36 (m, 4H), 2.45 (m,1H), 2.40 (m, 4H), 2.20 (s, 3H), 0.94 (m, 2H), 0.75 (m, 2H); LC-MS (ESI)m/z: 261.3 (M+H⁺).

General Method F: Suzuki Coupling Reaction Intermediate C-I-12:1-methyl-4-(4-nitro-3-vinylphenyl) piperazine

A mixture of 1-(3-bromo-4-nitrophenyl)-4-methylpiperazine (B-I-8, 30 g,100 mmol) and potassium trifluorovinyl borate (20 g, 150 mmol) in DMSO(210 mL) was treated with K₂CO₃ (42 g, 301 mmol) at rt and the reactionmixture was purged with nitrogen for 15 min. PdCl₂(dppf) (3.7 g, 5.0mmol) was added into the reaction mixture and the reaction mixture wasstirred at 80° C. for 3 h. The reaction mixture was diluted with coldwater (300 mL) and the solution was extracted with EtOAc (3×250 mL). Thecombined organic extracts were washed with brine (200 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Thecrude was purified by silica gel column chromatography (0 to 80%EtOAc/hexane, 10 CV's) to obtain 1-methyl-4-(4-nitro-3-vinylphenyl)piperazine. (20 g, 81% yield) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 7.96 (d, J=9.2 Hz, 1H), 7.21 (m, 1H), 6.98 (m, 2H), 5.77 (t,J=17.2 Hz, 1H), 5.41 (d, J=11.2 Hz, 1H), 3.44 (t, J=4.8 Hz, 4H), 2.42(t, J=4.8 Hz, 4H), 2.21 (s, 3H); LC-MS (ESI) m/z: 247.3 (M+H⁺).

The General Method E or General Method F for the Suzuki reaction wasused to prepare the following intermediates in Table C.

TABLE C Yield ¹H NMR (400 MHz, LC-MS Intermediate Structure Method (%)DMSO-d₆): δ (m/z: (M + H⁺) C-I-2

E 43 7.90 (d, J = 9.3 Hz, 1H), 6.84 (dd, J = 9.3 and 2.7 Hz, 1H), 6.53(d, J = 2.7 Hz, 1H), 3.36- 3.45 (m, 8H), 2.44-2.47 (m, 1H), 1.41 (s,9H), 0.93-0.97 (m, 2H), 0.73-0.76 (m, 2H). No MS Data C-I-3

E 91 No NMR Data 276.2 C-I-4

E 62 7.83 (d, J = 5.9 Hz, 1H), 6.63 (d, J = 5.9 Hz, 1H), 3.21 (s, 4H),2.43 (s, 4H), 2.38 (m, 1H), 2.20 (s, 3H), 0.96 (m, 2H), 0.74 (m, 2H).280.2 C-I-5

E 53 7.91 (d, J = 9.2 Hz, 1H), 6.84 (m, 1H), 6.49 (m, 1H), 3.98 (s, 2H),3.68 (m, 2H), 3.45 (m, 2H), 2.9 (s, 3H), 2.47 (s, 1H), 0.94 (m, 2H),0.78 (m, 2H). 276.1 C-I-6

E 78 7.91 (d, J = 9.2 Hz, 1H), 6.84 (m, 1H), 6.49 (m, 1H), 3.98 (s, 2H),3.68 (m, 2H), 3.45 (m, 2H), 2.8 (s, 3H), 2.47 (s, 1H), 0.94 (m, 2H),0.78 (m, 2H). 276.1 C-I-7

E 44 7.91 (d, J = 9.3 Hz, 1H), 6.66 (dd, J = 2.6 and 9.4 Hz 1H), 6.32(d, J = 2.4 Hz, 1H), 3.59 (m, 2H), 3.53 (m, 2H), 3.28 (m, 1H), 2.58 (m,2H), 2.44 (m, 2H), 2.24 (s, 3H), 1.87 (m, 2H), 0.95 (dd, J = 1.6 and 8.4Hz, 2H), 0.73 (m, 2H). 276.1 C-I-8

E 93 7.90 (d, J = 9.3 Hz, 1H), 6.86 (dd, J = 9.3 and 2.6 Hz, 1H), 6.55(d, J = 2.6 Hz, 1H), 3.70 (t, J = 4.8 Hz, 4H), 3.30-3.33 (m, 4H),2.46-2.48 (m, 1H), 0.93-0.96 (m, 2H), 0.73-0.76 (m, 2H). No Data C-I-9

E 58 7.89 (d, J = 8.5 Hz, 1H), 6.87 (m, 1H), 6.55 (d, J = 2.6 Hz, 1H),3.99 (m, 2H), 2.97-3.04 (m, 2H), 2.88 (m, 1H), 2.55 (m, 1H), 2.45-2.47(m, 1H), 2.15 (m, 1H), 2.05 (m, 1H), 1.95 (m, 1H), 1.80-1.85 (m, 1H),1.63-1.74 (m, 2H), 1.35 (m, 1H), 0.92-0.96 (m, 2H), 0.72-0.75 (m, 2H).288.2 C-I-10

E 64 7.91 (d, J = 9.2 Hz, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 4.55 (s, 1H),3.48 (s, 1H), 2.80 (d, J = 9.5 Hz, 1H), 2.53 (m, 1H), 2.41 (d, J = 9.8Hz, 1H), 2.27 (s, 3H), 1.89 (d, J = 9.3 Hz, 1H), 1.73 (d, J = 9.7 Hz,1H), 0.94 (m, 2H), 0.71 (m, 2H). 274.2 C-I-11

E 78 7.90 (d, J = 9.0 Hz, 1H), 6.28 (dd, J = 9.1 and 2.4 Hz, 1H), 6.01(s, 1H), 4.01 (t, J = 7.8 Hz, 2H), 3.75 (dd, J = 8.6 and 5.2 Hz, 2H),3.12 (m, 1H), 2.10 (s, 6 H), 0.95 (m, 2H), 0.8 (m, 2H). 262.2 C-I-13

F 87 7.98 (d, J = 9.3 Hz, 1H), 7.21 (dd, J = 17.2 and 10.9 Hz, 1H),6.95-6.97 (m, 2H), 5.79 (d, J = 17.2 Hz, 1H), 5.42 (d, J = 11.0 Hz, 1H),3.46 (s, 8H), 1.41 (s, 9H). 356.2 (M + Na + H⁺). C-I-14

F 77 No NMR Data 262.2 C-I-15

F 96 No NMR Data 276.2 C-I-16

F 90 7.98 (d, J = 9.0 Hz, 1H), 7.21 (dd, J = 17.3 and 10.9 Hz, 1H), 7.00(m 1H), 6.98 (s, 1H), 5.80 (d, J = 17.2 Hz, 1H), 5.42 (d, J = 11.0 Hz,1H), 3.72 (t, J = 4.8 Hz, 4H), 3.41 (t, J = 4.8 Hz, 4H). 235.2 C-I-17

F 81 8.01 (d, J = 9.1 Hz, 1H), 7.25 (dd, J = 17.3 and 10.9 Hz, 1H),6.62-6.65 (m, 2H), 5.78 (d, J = 17.3 Hz, 1H), 5.41 (d, J = 11.0 Hz, 1H),3.73-3.77 (m, 1H), 3.46-3.70 (m, 4H), 2.35-2.43 (m, 1H), 2.24-2.31 (m,1H). No Data C-I-18

F 72 8.01 (d, J = 9.1 Hz, 1H), 7.25 (dd, J = 17.3 and 10.9 Hz, 1H),6.62-6.65 (m, 2H), 5.78 (d, J = 17.3 Hz, 1H), 5.41 (d, J = 11.0 Hz, 1H),3.73-3.77 (m, 1H), 3.46-3.70 (m, 4H), 2.35-2.43 (m, 1H), 2.24-2.31 (m,1H). No Data C-I-19

F 32 7.99 (d, J = 9.2 Hz, 1H), 7.24 (m, 1H), 6.96 (m, 2H), 5.86 (d, J =18.1 Hz, 1H), 5.44 (d, J = 11.9 Hz, 1H), 4.05 (s, 2H), 3.75 (t, J = 5.2Hz, 2H), 3.47 (t, J = 5.4 Hz, 2H), 2.91 (s, 3H). 262.2 C-I-20

F 42 7.99 (d, J = 9.2 Hz, 1H), 7.22 (m, 1H), 6.96 (m, 2H), 5.85 (m, 1H),5.44 (d, J = 11.0 Hz, 1H), 4.04 (s, 2H), 3.75 (t, J = 5.2 Hz, 2H), 3.47(t, J = 5.6 Hz, 2H), 2.92 (s, 3H). 262.3 C-I-21

F 87 7.96 (d, J = 9.3 Hz, 1H), 7.23 (dd, J = 17.2 and 10.9 Hz, 1H), 6.84(m, 2H), 5.76 (d, J = 17.2 Hz, 1H), 5.39 (d, J = 11.0 Hz, 1H), 3.60 (d,J = 11.4 Hz, 2H), 3.23 (brs, 2H), 3.03 (d, J = 11.4 Hz, 2H), 2.23 (s,3H), 1.95 (m, 2H), 1.56 (m, 2H). 274.2 C-I-22

F 56 No NMR Data 260.2 C-I-23

F 95 7.96 (d, J = 9.3 Hz, 1H), 7.21 (dd, J = 17.2 and 10.9 Hz, 1H), 7.00(dd, J = 9.4 and 2.9 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 5.79 (dd, J =17.2 and 1.2 Hz, 1H), 5.41 (d, J = 11.0 Hz, 1H), 4.15 (d, J = 12.1 Hz,1H), 3.99 (d, J = 12.6 Hz, 1H), 2.91-3.06 (m, 3H), 2.62 (t, J = 11.2 Hz,1H), 2.18 (td, J = 11.3 and 3.3 Hz, 1H), 2.06 (q, J = 8.7 Hz, 1H), 1.98(m, 1H), 1.84 (m, 1H), 1.63-1.76 (m, 2H), 1.34- 1.42 (m, 1H). 274.2C-I-24

F 100 7.96 (d, J = 9.3 Hz, 1H), 7.21 (dd, J = 17.2 and 10.9 Hz, 1H),7.00 (dd, J = 9.4 and 2.9 Hz, 1H), 6.96 (d, J = 2.8 Hz, 1H), 5.79 (dd, J= 17.2 and 1.2 Hz, 1H), 5.41 (dd, J = 11.0 and 1.2 Hz, 1H), 4.15 (d, J =12.1 Hz, 1H), 3.99 (d, J = 12.6 Hz, 1H), 3.06 (d, J = 11.2 Hz, 1H),2.92- 3.03 (m, 2H), 2.62 (t, J = 11.2 Hz, 1H), 2.17 (td, J = 11.3 and3.3 Hz, 1H), 2.06 (q, J = 8.7 Hz, 1H), 1.98 (m, 1H), 1.84 (m, 1H),1.63-1.74 (m, 2H), 1.37 (m, 1H). 274.2 C-I-25

F 79 7.90 (d, J = 13.6 Hz, 1H), 7.06- 7.15 (m, 2H), 5.83 (d, J = 17.3Hz, 1H), 5.47 (d, J = 11.0 Hz, 1H), 3.26-3.30 (m, 4H), 2.44- 2.47 (m,4H), 2.22 (s, 3H). 266.2 C-I-26

F 75 7.98 (d, J = 9.4 Hz, 1H), 7.27 (m, 1H), 6.80 (dd, J = 2.9 and 9.3Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 5.70 (d, J = 18.4 Hz, 1H), 5.39 (d, J= 11.2 Hz, 1H), 3.66 (m, 2H), 3.59 (m, 2H), 2.63 (m, 2H), 2.45 (m, 2H)2.25 (s, 3H), 1.89 (m, 2H). 262.2 C-I-27

F 92 7.98 (d, J = 9.4 Hz, 1H), 7.26 (dd, J = 17.2 and 10.9 Hz, 1H), 6.84(d, J = 9.6 Hz, 1H), 6.77 (d, J = 9.1 Hz, 1H), 5.75 (d, J = 17.2 Hz,1H), 5.42 (d, J = 11.0 Hz, 1H), 3.52-3.81 (m, 6H), 3.23-3.31 (m, 2H),1.72-1.90 (m, 2H), 1.22 (s, 9H). C-I-28

F 57 7.93 (d, J = 9.3 Hz, 1H), 6.95 (dd, J = 2.7 and 9.3 Hz, 1H), 6.69(d, J = 2.7 Hz, 1H), 5.07 (s, 1H), 4.83 (s, 1H), 3.40 (brs, 4H), 2.41(brs, 4H), 2.21 (s, 3H), 1.82 (s, 3H). 262.3 C-I-29

F 88 7.93 (d, J = 9.2 Hz, 1H), 6.94 (m, 1H), 6.69 (d, J = 2.0 Hz, 1H),5.07 (s, 1H), 4.83 (s, 1H), 3.40 (m, 4H), 2.45 (m, 4H), 2.35 (q, J = 6.8Hz, 2H), 1.98 (s, 3H), 1.02 (t, J = 6.8 Hz, 3H). 276.3 C-I-30

F 92 7.90 (d, J = 9.2 Hz, 1H), 6.94 (d, J = 9.3 Hz, 1H), 6.72 (d, J =2.2 Hz, 1H), 5.71 (s, 1H), 3.37 (m, 4H), 2.41 (m, 8H), 2.20 (s, 3H),1.95 (m, 2H). 289.2 C-I-31

F 91 7.97 (d, J = 9.3 Hz, 1H), 7.24 (dd, J = 17.2 and 10.9 Hz, 1H), 6.61(d, J = 23.0 Hz, 2H), 5.73 (d, J = 17.2 Hz, 1H), 5.38 (d, J = 11.0 Hz,1H), 4.60 (s, 1H), 3.49 (s, 1H), 3.31 (s, 2H), 2.82 (dd, J = 9.6 and 2.0Hz, 1H), 2.44 (m, 1H), 2.28 (s, 3H), 1.71-1.90 (m, 2H). 260.2 C-I-32

F 63 No NMR Data 262.2 C-I-34

F 74 No NMR Data 262.2 C-I-35

F 63 No NMR Data 262.2 C-I-36

E 89 7.90 (d, J = 9.2 Hz, 1H), 6.78 (dd, J = 2.5 and 9.3 Hz, 1H), 6.47(s, 1H), 4.51 (brm, 2 H), 3.61 (brm, 2 H), 3.05 (brm, 1H), 2.90 (brm,1H), 1.93 (s, 2H), 1.71 (m, 2H), 1.38 (s, 9H), 0.94 (m, 2 H), 0.75 (m,2H). 396.2 (M + Na + H⁺). C-I-37

E crude No data 288.2 C-I-38

E 68 No Data 276.2

General Method G: Reduction Intermediate D-I-1:2-cyclopropyl-4-(4-methylpiperazin-1-yl) aniline

A solution of 1-(3-cyclopropyl-4-nitrophenyl)-4-methylpiperazine (C-I-1,12 g, 46 mmol) in MeOH (60 mL) at 0° C., was treated with NH₄Cl (73 g,14 mmol) and the reaction mixture was stirred at 0° C. for 10 min. Zincdust (30 g, 459 mmol) was added slowly (internal temperature increasedto 20° C.) into the reaction mixture under an ice-water bath. After 15minutes of stirring, the reaction mixture was warmed to rt and allowedto stir vigorously at rt for 16 h. The mixture was filtered through apad of Celite and washed with THF (500 mL). The filtrate wasconcentrated under reduced pressure to afford2-cyclopropyl-4-(4-methylpiperazin-1-yl) aniline (10 g, 95%) as a darkbrown sticky solid. ¹H NMR (400 MHz, DMSO-d₆): δ 6.52 (m, 2H), 6.43 (d,J=2.0 Hz, 1H), 4.52 (brs, 2H), 2.88 (m, 4H), 2.42 (m, 4H), 2.20 (s, 3H),1.65 (m, 1H), 0.813 (m, 2H), 0.471 (m, 2H); LC-MS (ESI) m/z: 213.2(M+H⁺).

General Method H: Reduction Intermediate D-I-11:2-ethyl-4-(4-methylpiperazin-1-yl)aniline

A solution of 1-methyl-4-(4-nitro-3-vinylphenyl) piperazine (C-I-12, 20g, 81 mmol) in EtOAc (200 mL) was treated with Pd/C (20 g, 10% w/w, 50%moisture) under nitrogen atmosphere and the mixture was then stirredunder hydrogen balloon pressure at rt for 3 h. After general work up,2-ethyl-4-(4-methylpiperazin-1-yl)aniline (16 g, 90% yield) was obtainedas a brown sticky solid. ¹H NMR (400 MHz, DMSO-d₆): δ 6.61 (s, 1H), 6.52(m, 2H), 4.25 (brs, 2H), 2.89 (t, J=4.4 Hz, 4H), 2.41 (m, 6H), 2.19 (s,3H), 1.09 (t, J=7.6 Hz, 3H); LC-MS (ESI) m/z: 219.3 (M+H⁺).

Using the General Method G or H for preparing D-I-1 or D-I-11, thefollowing intermediates in Table D were prepared.

TABLE D LC-MS Yield ¹H NMR (400 MHz, (m/z: Intermediate Structure Method(%) DMSO-d₆): δ (M + H⁺) D-I-2

G 76 6.56 (d, J = 8.6 Hz, 1H), 6.51 (d, J = 8.5 Hz, 1H), 6.45 (s, 1H),4.53 (s, 2H), 3.39 (s, 4H), 2.80 (s, 4H), 1.63 (s, 1H), 1.39 (s, 9H),0.80 (d, J = 8.0 Hz, 2H), 0.47 (d, J = 5.2 Hz, 2H). No Data D-I-3

G 100 6.51-6.56 (m, 2H), 6.43 (s, 1H), 4.49 (s, 2H), 3.67 (t, J = 4.6Hz, 4H), 2.85 (t, J = 4.5 Hz, 4H), 1.65 (m, 1H), 0.80 (m, 2H), 0.46 (m,2H). 219.2 D-I-4

G 100 6.49 (d, J = 5.1 Hz, 1H), 6.38 (d, J = 5.1 Hz, 1H), 4.85 (s, 2H),2.80 (s, 4H), 2.40 (s, 4H), 2.18 (s, 3H), 0.80 (m, 2H), 0.44 (m, 2H).250.2 D-I-5

G 96 6.56 (m, 2H), 6.46 (s, 1H), 4.56 (s, 2H), 3.48 (s, 2H), 3.32 (s,2H), 3.18 (s, 2H), 2.85 (s, 3H), 1.65 (m, 1H), 0.83 (m, 2H), 0.50 (m,2H). 246.1 D-I-6

G 70 6.55 (m, 2H), 6.46 (s, 1H), 4.55 (brs, 2H), 3.48 (s, 2H), 3.32 (s,2H), 3.17 (s, 2H), 2.85 (s, 3H), 1.65 (s, 1H), 0.82 (m, 2H), 0.50 (m,2H). 246.2 D-I-7

G 74 6.63 (m, 1H), 6.46 (m, 1H), 6.27 (s, 1H), 3.54 (brm, 2H), 3.32 (m,6H) 3.16 (m, 2H), 2.82 (s, 3H), 2.11 (brs, 2H), 1.70 (s, 1H), 0.84 (brm,2H), 0.51 (brm, 2H). 246.2 D-I-8

G 100 6.57 (m, 2H), 6.44 (m, 1H), 4.48 (brs, 2H), 3.40 (m, 1H), 3.26 (m,1H), 2.96 (m, 2H), 2.56 (m, 1 H), 2.18-2.26 (m, 2H), 2.04 (m, 2H),1.62-1.80 (m, 4H), 1.32 (m, 1H), 0.81 (m, 2H), 0.45 (m, 2 H). 258.2D-I-9

G 91 6.51 (d, J = 8.6 Hz, 1H), 6.24 (s, 1H), 6.08 (s, 1H), 4.19 (s, 1H),3.63 (s, 1H), 3.31 (s, 2H), 3.05-3.05 (m, 1H), 2.80 (brs, 2H), 2.39 (s,3H), 1.91 (s, 1H), 1.81 (s, 1H), 1.66 (brs, 1H), 0.81 (m, 2H), 0.46 (m,2H). 244.2 D-I-10

G 100 No NMR Data 232.2 D-I-12

H 100 6.65 (d, 2H), 6.46 (d, J = 8.5 Hz, 2H), 4.53 (s, 2H), 2.83 (t, J =4.8 Hz, 4H), 2.62 (t, J = 4.8 Hz, 4H), 1.62 (m, 1H), 0.40 (m, 2H), 0.29(m, 2H). 218.2 D-I-13

H 92 6.50 (d, J = 8.0 Hz, 1H), 6.29 (brs, 1H), 6.24 (d, J = 7.6 Hz, 1H),4.50 (s, 1H), 4.31 (s, 1H), 4.11 (brs, 2H), 3.64 (brs, 2H), 3.39 (m,1H), 2.79 (d, J = 8.8 Hz, 1H), 2.01 (s, 3H), 1.85 (m, 1H), 1.74 (m, 1H).205.1 D-I-14

H 100 No NMR Data 292.2 D-I-15

H 72 6.48 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 7.2 Hz, 1H), 6.35 (m, 1H),4.07 (brs, 2H), 3.33-3.48 (m, 4H), 3.00-3.31 (m, 2H), 2.52- 2.71 (m,1H), 2.00 (s, 3H), 1.43-1.80 (m, 3H), 1.31 (s, 9H). 306.2 D-I-16

H 82 split into two isomers. 320.2 D-I-17

H 97 6.58 (brs, 1H), 6.52 (m, 2H), 4.34 (brs, 2H), 2.88 (m, 4H), 2.49(m, 4H), 2.19 (s, 3H), 2.01 (s, 3H). 206.1 D-I-18

H 100 6.58 (s, 1H), 6.48-6.53 (m, 2H), 4.59 (t, J = 4.9 Hz, 1H), 4.50(t, J = 4.9 Hz, 1H), 4.35 (brs, 2H), 2.89 (t, J = 4.7 Hz, 4H), 2.67 (t,J = 4.7 Hz, 1H), 2.61 (t, J = 4.8 Hz, 1H), 2.55 (t, J = 4.7 Hz, 4H),2.01 (s, 3H). 238.2 D-I-19

H 44 6.58 (s, 1H), 6.49 (m, 2H), 4.33 (brs, 2H), 2.84 (brs, 4H), 2.63(brs, 4H), 2.01 (s, 3H), 1.62 (m, 1H), 0.42 (m, 2H), 0.31 (m, 2H). 232.3D-I-20

H 99 No NMR Data 292.2 D-I-21

H 92 6.49 (m, 2H), 6.27 (dd, J = 2.0 and 8.0 Hz, 1H), 4.19 (brs, 2H),3.73 (s, 3H), 2.93 (m, 4H), 2.42 (m, 4H), 2.20 (s, 3H). 222.1 D-I-22

H 100 6.52 (d, J = 8.4 Hz, 1H), 6.46 (m, 1H), 6.28 (m, 1H), 4.46 (m,1H), 4.25 (brs, 2H), 2.91 (m, 4H), 2.41 (m, 4H), 2.13 (s, 3H), 1.17 (d,J = 8.4 Hz, 6H) 250.3 D-I-23

H 100 6.63 (m, 1H), 6.53 (m, 2H), 4.39 (brs, 2H), 3.41 (brs, 4H), 2.83(brs, 4H), 2.30 (q, 2H), 1.40 (s, 9H), 1.09 (t, J = 7.4 Hz, 3H). 306.2D-I-24

H 92 6.63 (s, 1H), 6.52 (s, 2H), 4.47 (brs, 2H), 2.91 (m, 5H), 2.42(brs, 4H), 2.19 (s, 3H), 1.12 (d, J = 6.8 Hz, 6H). 234.2 D-I-25

H 93 6.63 (s, 1H), 6.51 (m, 2H), 4.37 (brs, 2H), 2.92 (m, 5H), 2.47 (m,4H), 2.33 (q, J = 7.2 Hz, 2H), 1.12 (d, J = 6.8 Hz, 6H), 1.01 (t, J =7.2 Hz, 3H). 248.3 D-I-26

H 100 No NMR Data 207.2 D-I-27

H 98 6.52 (d, J = 8.5 Hz, 1H), 6.26-6.30 (m, 2H), 4.16 (s, 2H),3.24-3.45 (m, 4H), 3.10-3.14 (m, 1H), 2.41 (q, J = 7.8 Hz, 2H),2.28-2.32 (m, 1H), 2.13-2.17 (m, 1H), 1.10 (t, J = 7.6 Hz, 3H). 216.2D-I-28

H 95 6.52 (d, J = 8.5 Hz, 1H), 6.26-6.30 (m, 2H), 4.16 (s, 2 H),3.24-3.45 (m, 4H), 3.10-3.14 (m, 1H), 2.41 (q, J = 7.8 Hz, 2H), 2.30 (m,1H), 2.13-2.17 (m, 1H), 1.10 (t, J = 7.6 Hz, 3H). 216.2 D-I-29

H 91 No NMR Data 238.2 D-I-30

H 87 6.49 (brs, 1H), 6.40 (m, 2H), 3.48 (m, 6H), 2.57 (m, 2H), 2.45 (m,4H) 2.30 (s, 3H), 1.85 (m, 2H), 1.09 (t, J = 7.6 Hz, 3H). 233.2 D-I-31

H 100 No NMR Data 246.2 D-I-32

H 97 6.45-6.50 (m, 3H), 4.28 (brs, 2H), 3.94 (s, 1H), 2.91 (m, 2H), 2.81(m, 1H), 2.75 (t, J = 7.5 Hz, 3H), 2.62 (m, 1H), 2.4-2.5 (m, 1H), 2.39(q, J = 7.5 Hz, 2H), 1.57 (m, 2H), 1.09 (t, J = 7.5 Hz, 3H). 232.2D-I-33

H 85 No NMR Data 246.2 D-I-34

H 100 No NMR Data 246.2 D-I-35

H 76 6.66 (m, 2H), 6.51 (s, 1H), 4.57 (brs, 2H), 2.96 (m, 4H), 2.89 (m,8H), 2.43 (s, 3H), 2.20 (m, 3H), 1.90 (m, 2H). 260.3 D-I-36

H 88 6.90 (s, 1H), 6.77 (m, 1H), 6.50 (s, 1H), 4.75 (brs, 2H), 3.98 (s,2H), 2.82 (s, 4H), 2.16 (m, 2H), 1.95 (m, 1H), 1.88 (m, 1H), 1.81 (m,1H), 1.32 (t, J = 7.4 Hz, 3H). 234.2 D-I-37

H 77 6.89 (s, 1H), 6.78 (m, 1H), 6.52(s, 1H), 4.93 (brs, 2H), 3.39 (s,2H), 2.86 (s, 4H), 2.16 (m, 2H), 1.98 (m, 1H), 1.89 (m, 1H), 1.80 (m,1H), 1.35 (t, J = 7.5 Hz, 3H). 234.2 D-I-38

H 77 No NMR Data 232.2 D-I-39

H 90 7.56 (s, 1H), 6.48 (s, 1H), 4.33 (brs, 2H), 3.21 (brs, 4H), 2.41(q, 2H), 2.37 (brs, 4H), 2.19 (s, 3H), 1.11 (t, J = 7.4 Hz, 3H). 221.1D-I-40

H 92 7.57 (s, 1H), 6.53 (s, 1H), 4.37 (brs, 2H), 3.67 (brs, 4H), 3.16(brs, 4H), 2.05 (s, 3H). 194.2 D-I-41

H 96 7.55 (s, 1H), 6.52 (s, 1H), 4.33 (brs, 2H), 3.33 (brs, 4H), 2.31(brs, 4H), 2.19 (s, 3H), 2.02 (s, 3H). 207.2 D-I-42

H 93 No NMR Data 232.2 D-I-43

H 80 6.76 (m, 1H), 6.66 (m, 2H), 6.56 (d, J = 8.4 Hz, 1H), 6.47 (d, J =8.6 Hz, 1H), 4.27 (s, 2H), 3.23 (s, 3H), 2.90 (brs, 4H), 2.41 (brs, 4H),2.19 (s, 3H). 236.3 D-I-44

G 96 No NMR data 226.2 D-I-45

H 100 No NMR Data 234.0 D-I-46

H 93 No NMR Data 234.2 D-I-47

H 100 No NMR Data 234.2 D-I-48

G 82 No NMR Data No data D-I-49

G 88 No NMR Data 258.2 D-V-1

H 100 6.74 (brm, 1H), 6.71 (m, 1H), 6.49 (m, 1H), 4.57 (brs, 2H), 4.00(brm, 2H), 2.73 (brm, 2H), 2.33 (m, 1H), 1.99 (s, 3H), 1.83 (m, 2H),1.38 (s, 9H), 1.32 (m, 2H). 313.2 (M + Na + H⁺). D-V-2

H 100 6.99 (brm, 1H), 6.95 (m, 1H), 6.54 (m, 1H), 5.85 (brm, 1H), 4.82(brs, 2H), 3.92 (brm, 2H), 3.16 (s, 3H), 2.96 (brm, 2H), 2.54 (m, 2H),2.38 (m, 2H), 2.03 (s, 3H). 185.2 D-V-3

H 93 7.84 (s, 1H), 7.62 (s, 1H), 7.11 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H),6.57 (d, J = 8.0 Hz, 1H), 4.76 (brs, 2H), 3.80 (s, 3H), 2.02 (s, 3H).188.4 D-V-4

H 93 7.51 (s, 1H), 7.32 (s, 1H), 7.26 (m, 2H), 6.57 (d, J = 8.1 Hz, 1H),4.78 (brs, 2H), 3.64 (s, 3H), 2.07 (s, 3H). 264.2 D-V-5

Grignard crude No NMR Data 250.2

Intermediate D-V-6: 2-ethyl-4-(1-methylpyrrolidin-3-yl)aniline

A solution of tert-butyl3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate(0.25 g, 0.85 mmol),4-bromo-2-ethylaniline (0.121 g, 0.60 mmol) in amixture of 1,4-dioxane (5 mL) and water (1 mL) was treated with K₂CO₃(0.251 g, 1.8 mmol). The mixture was degassed with Ar for 2 min and thenbis(triphenylphosphine)palladium(II) dichloride (0.042 g, 0.06 mmol) wasadded. The reaction mixture was heated at 95° C. overnight undermicrowave. The reaction mixture was cooled to rt and the mixtureextracted with EtOAC (2x). The combined organic extracts were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toobtain the crude. The crude was purified by silica gel columnchromatography (0 to 60% EtOAc/hexanes, 15CVs) to give tert-butyl3-(4-amino-3-ethylphenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.12 g,70% yield) which was carried forward without further purification. LC-MSm/z: 289.2 (M+H⁺).

A solution of tert-butyl3-(4-amino-3-ethylphenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (0.12 g,0.42 mmol) in MeOH (20 mL) was treated with Pd-C(0.040 g, 0.0424 mmol).The reaction mixture was under a balloon overnight. The mixture wasfiltered through a pad of celite and the filtrate was concentrated underreduced pressure to give tert-butyl3-(4-amino-3-ethylphenyl)pyrrolidine-1-carboxylate (0.12 g, 97% yield)as a colorless sticky oil. ¹H NMR (400 MHz, DMSO-d₆): δ 6.81 (s, 1H),6.80 (m, 1H), 6.53 (d, J=8.0 Hz, 1H), 4.68 (s, 2H), 3.57 (m, 1H), 3.41(m, 1H), 3.11-3.29 (m, 2H), 3.04 (m, 1H), 2.40 (q, J=7.5 Hz, 2H), 2.08(brm, 1H), 1.75 (brm, 1H), 1.39 (s, 9H), 1.09 (t, J=7.5 Hz, 3H); LC-MSm/z: 313.2 (M+H+Na⁺).

A solution of tert-butyl3-(4-amino-3-ethylphenyl)pyrrolidine-1-carboxylate (0.12 g, 0.40 mmol)in a biphasic mixture of EtOAc (25 mL) and Sat′d NaHCO₃ (aq) (25 mL) wastreated with benzyl chloroformate (0.086 mL, 0.60 mmol). The mixture wasstirred at rt overnight. The mixture was partitioned between EtOAc andsat'd NaHCO₃ and extracted EtOAc (2×25 mL). The combined organicextracts were dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to obtain tert-butyl3-(4-(((benzyloxy)carbonyl)amino)-3-ethylphenyl)pyrrolidine-1-carboxylate(0.18 g, 100% yield) which was carried forward without furtherpurification. LC-MS m/z: 447.2 (M+H+Na⁺).

A solution of tert-butyl3-(4-(((benzyloxy)carbonyl)amino)-3-ethylphenyl)pyrrolidine-1-carboxylate(0.18 g, 0.44 mmol) in DCM (3 mL) was treated with TFA (2 mL). Themixture was stirred for 1 h at rt. The solvent was removed to give thecrude TFA salt. The crude was suspended in DCM and TEA (1 mL) was added.The solvent was removed under reduced pressure and dried under vacuum.The resulting mixture was suspended in DCM and AcOH (3 drops).Formaldehyde (5 drops) was added and the mixture was stirred at rt for 1h. Sodium triacetoxyborohydride (0.37 g, 1.7 mmol) was added and themixture was stirred overnight at rt. The mixture was partitioned betweenDCM and sat′d NaHCO₃ and stirred for 1 h. The mixture was extracted withDCM (2×25 mL). The combined organic extracts were dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give benzyl(2-ethyl-4-(1-methylpyrrolidin-3-yl)phenyl)carbamate (0.14 g, 94% yield)which was carried forward without further purification. LC-MS m/z: 339.2(M+H⁺).

A solution of benzyl(2-ethyl-4-(1-methylpyrrolidin-3-yl)phenyl)carbamate (0.14 g, 0.41 mmol)in EtOAc (20 mL) was flushed with Ar. Palladium on carbon (0.022 g, 0.02mmol) was added and the mixture was hydrogenated under a balloonovernight at rt. The mixture was filtered through a pad of celite andthe filtrate was concentrated under reduced pressure to give(2-ethyl-4-(1-methylpyrrolidin-3-yl)aniline (0.10 g, 119% yield) whichwas carried forward without further purification. LC-MS m/z: 205.2(M+H⁺).

General Method of Alkylation of Z Lactams and Deprotection of Boc GroupIntermediate H-VII-1

A solution of 1, 4-oxazepan-5-one (10 g, 87 mmol) in dry THF (400 mL) at0° C. was treated with sodium hydride (3.0 g, 130 mmol) portion wiseunder nitrogen atmosphere. The reaction mixture was stirred for 15 minat 0° C. then tert-butyl (3-bromopropyl) carbamate (21 g, 87 mmol) wasadded. The solution was continued stirred from 0° C. rt for 16 h. Thereaction mixture was quenched with saturated solution of NH₄Cl (200 mL)and then the solution was extracted with EtOAc (2×150 mL). The combinedorganic extract was washed with brine (150 mL), dried over anhydrousNa₂SO₄, and filtered under reduced pressure. The crude was purified bysilica gel column chromatography (40 to 50% EtOAc/hexane, 15 CV's) toobtain tert-butyl (3-(5-oxo-1,4-oxazepan-4-yl)propyl carbamate (12 g,50% yield) as yellow liquid. The product was dissolved in DCM (50 mL)and treated with 4 N HCl in 1,4-dioxane (4 eq). The mixture was stirredat rt for 3 h and concentrated, dried under high vacuum to obtain4-(3-aminopropyl)-1,4-oxazepan-5-one HCl salt (100% yield). ¹H NMR (400MHz, DMSO-d₆): δ 8.09 (brs, 3H), 3.62 (m, 4H), 3.49 (m, 2H), 3.35 (t,J=6.8 Hz, 2H), 2.73 (m, 2H), 2.62 (t, J=4.8 Hz, 2H), 1.78 (m, 2H); MS(ESI) m/z: 173.2 (M+H⁺).

Using the General Method for the preparation of H-VII-1, the followingintermediates H-II-1 through H-VI-1 in Table E were prepared.

TABLE E LC-MS Yield (m/z: Intermediate Structure (%) ¹H NMR (400 MHz,DMSO-d₆): δ (M + H⁺) H-I-1

crude No Data 157.2 H-II-1

52 Boc: 4.17 (m, 2H), 3.26 (m, 2H), 2.52 (m, 2H), 2.23 (m, 2H), 1.80 (m,2H), 1.71 (m, 2H), 1.39 (s, 6H), 1.17 (s, 9H). 171.2 H-III-1

36 Boc: 6.76 (t, J = 5.7 Hz, 1H), 3.20 (m, 4H), 2.86 (m, 2H), 2.17 (m,2H), 1.67 (m, 4H), 1.53 (m, 2H), 1.35 (s, 9H). 157.2 H-IV-1

64 Boc: 4.14 (m, 2H), 3.25 (m, 2H), 3.18 (m, 2H), 2.92 (m, 2H), 1.92 (m,2H), 1.62 (m, 2H), 1.36 (s, 9H). 159.2 H-XIII-1

84 Boc: 3.99 (m, 2H), 3.48 (m, 2H), 3.30 (m, 4H), 2.91 (m, 2H), 1.58 (m,2H), 1.36 (s, 9H). 159.2 H-VI-1

57 Boc: 6.73 (s, 1H), 4.08 (s, 2H), 3.73 (t, J = 5.5 Hz, 2H), 3.46 (m,2H), 3.25 (m, 2H), 2.88 (q, J = 6.5 Hz, 2H), 1.98 (s, 1H), 1.78 (m, 2H),1.53 (m, 2H), 1.36 (s, 9H). 173.2 H-IV-2

crude No NMR Data 187.2 H-VII-2

crude No NMR Data 201.2

Intermediate H-XIV: 1-(3-aminopropyl) azepan-2-one

A suspension of DBU (22 g, 145 mmol) in MeOH: H₂O (1:1) (130 mL) wastreated with KOH (12 g, 217 mmol) at 0° C. under N₂ atmosphere and thereaction mixture was stirred at rt for 16 h. The reaction mixture wasevaporated under reduced pressure and the residue was diluted with water(200 mL). The solution was extracted with 10% MeOH in DCM (3×250 mL) andthe combined organic extracts were dried over anhydrous sodium sulphate,filtered and concentrated under reduced pressure to obtain1-(3-aminopropyl) azepan-2-one (21 g, 85% yield) as a liquid oil. ¹H NMR(400 MHz, CDCl3): δ 3.45 (t, J=3.5 Hz, 2H), 3.31 (t, J=4.4 Hz, 2H), 2.68(t, J=6.5 Hz, 2H), 2.51 (t, J=5.8 Hz, 2H), 1.70 (m, 2H), 1.65 (m, 8H);LC-MS (ESI) m/z: 171.4 (M+H⁺).

Intermediate L-III-1:2-chloro-5-cyclopropyl-4-(methylsulfonyl)pyrimidine

(A) A suspension of 5-bromo-2-chloro-4-(methylthio) pyrimidine (25.0 g,105 mmol) and cyclopropylboronic acid (13.7 g, 158 mmol) in toluene: H₂O(9:1) (650 mL) was treated with K₃PO₄ (66.7 g, 315 mmol) was added. Thereaction mixture was purged with nitrogen for 20 min and then addedtricyclohexyl phosphine (5.9 g, 21 mmol) and Pd(OAc)₂ (2.35 g, 10.50mmol). The reaction mixture was stirred at 90° C. for 16 h. The reactionmixture was diluted with water (200 mL) and extracted with EtOAc (3×300mL). The combined organic extracts were washed with brine (200 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude was purified by silica gel column chromatography (0to 10% EtOAc/hexane) to obtain 2-chloro-5-cyclopropyl-4-(methylthio)pyrimidine (14.0 g, 66% yield) as a yellow oil. ¹H NMR (400 MHz,DMSO-d₆): δ 7.92 (s, 1H), 2.58 (s, 3H), 1.67 (m, 1H), 1.03 (m, 2H), 0.67(m, 2H); LC-MS (ESI) m/z: 201.0 (M+H⁺).

(B) A solution of 2-chloro-5-cyclopropyl-4-(methylthio) pyrimidine (4.0g, 20 mmol) in DCM (60 mL) at 0° C. was treated with m-CPBA (4.8 g, 28mmol). The reaction mixture was warmed to rt and stirred for 3 h. Thereaction mixture was washed with saturated aq. NaHCO₃ (2×40 mL). Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to obtain2-chloro-5-cyclopropyl-4-(methylsulfonyl)pyrimidine (3.6 g, 86% yield)as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.57 (s, 1H), 2.89 (s,3H), 2.16 (m, 1H), 1.16 (m, 2H), 0.93 (m, 2H); LC-MS (ESI) m/z: 217.0(M+H⁺).

Intermediate L-I-2: 4-chloro-2-(methylthio)-5(trifluoromethyl)pyrimidine

A solution of 2,4-dichloro-5-(trifluoromethyl) pyrimidine (100 g, 0.46mol) in diethyl ether (2 L) was treated with ZnCl₂ (1.0 N in ether) (555mL, 0.56 mol) dropwise at 0° C. and the reaction mixture was stirred for2 h. Sodium thiomethoxide (49 g, 0.94 mol) was added at 0° C. and thereaction mixture was warmed to rt and stirred for 48 h. The reactionmixture was quenched with 2 N HCl under an ice-water bath and then thesolution was extracted with Et₂O (3×500 mL). The combined organicextracts were washed with water (500 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated under reduced pressure at 35° C. to obtain4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (100 g, 95% yield)as a colorless liquid. 41 NMR (400 MHz, DMSO-d₆): δ 9.01 (s 1H), 2.62 (s3H).

General Method for Substitution Reaction Intermediate J-7:4-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one

A solution of 4-(3-aminopropyl) 1,4-oxazepan-5-one hydrochloride(H-VII-1, 3.0 g, 17.4 mmol) in DMF (60 mL) was treated with DIEA (15.5ml, 87.2 mmol) at 0° C. and stirred for 15 min. Then4-chloro-2-(methylthio)-5-(trifluoromethyl) pyrimidine (L-I-2, 6.0 g,26.2 mmol) was added and stirring continued from 0° C. to rt for 16 h.The reaction mixture was quenched with ice water (120 mL) and extractedwith ethyl acetate (3×50 mL). The combined organic extracts were washedwith brine (50 mL), dried over anhydrous Na₂SO₄, and filtered. Thefiltrate was concentrated under reduced pressure and the crude waspurified by silica gel column chromatography (40 to 50% EtOAc/hexane, 15CV's) to obtain 4-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one (3.0 g, 47% yield) asyellow liquid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.25 (s, 1H), 7.52 (bs, 1H),3.64 (m, 4H), 3.47 (m, 2H), 3.42 (m, 2H), 3.32 (m, 2H), 2.63 (t, J=4.8Hz, 2H), 2.47 (s, 3H), 1.68 (m, 2H); LC-MS (ESI) m/z: 365.3 (M+H⁺).

Using the General Method for preparation of Intermediate J-7, thefollowing intermediates of Table F were prepared.

TABLE F LC-MS Yield ¹H NMR (400 MHz, DMSO-d₆): (m/z: IntermediateStructure (%) δ (M + H⁺) K-1

31 No NMR Data 323.2 K-2

82 7.69 (s, 1H), 7.51 (t, J = 5.9 Hz, 1H), 3.34 (t, J = 6.4 Hz, 3H),3.24 (m, 2H), 2.22 (t, J = 6.3 Hz, 2H), 1.68-1.73 (m, 6H), 1.46- 1.56(m, 2H), 0.86-0.90 (m, 2H), 0.54 (m, 2H). 309.2 K-3

47 7.69 (s, 1H), 7.43 (s, 1H), 4.17 (m, 2H), 3.39 (m, 2H), 3.29 (m, 4H),1.94 (m, 2H), 1.77 (m, 2H), 1.48 (m, 1H), 0.89 (m, 2H), 0.56 (m, 2H).311.3 K-4

42 7.69 (s, 1H), 7.45 (s, 1H), 3.66 (m, 4H), 3.56 (brs, 2H), 3.35 (m,4H), 2.64 (m, 2H), 1.69 (m, 2H), 1.50 (m, 1H), 0.88 (m, 2H), 0.56 (m,2H). 325.3 K-5

51 7.70 (s, 1H), 7.45 (brs, 1H), 4.12 (s, 2H), 3.76 (t, J = 5.2 Hz, 2H),3.50 (m, 2H), 3.37 (m, 4H), 1.85 (m, 2H), 1.72 (m, 2H), 1.51 (m, 1H),0.89 (m, 2H), 0.55 (m, 2H). 325.1 K-6

37 8.15 (s, 1H), 7.94 (m, 1H), 3.35 (m, 2H), 3.30 (m, 2H), 3.25 (m, 2H),2.21 (m, 2H), 1.72 (m, 6H). 303.20 K-7

64 8.15 (s, 1H), 7.90 (brs, 1H), 4.16 (m, 2H), 3.37 (m, 2H), 3.27 (m,4H), 1.94 (m, 2H), 1.77 (m, 2H). 305.2 K-8

47 8.20 (s, 1H), 7.88 (m, 1H), 4.11 (s, 2H), 3.76 (m, 2H), 3.50 (m, 2H),3.36 (m, 4H), 1.84 (m, 2H), 1.72 (m, 2H). 319.1 K-9

51 8.15 (s, 1H), 7.91 (brs, 1H), 3.65 (m, 4H), 3.48 (m, 2H), 3.35 (m,4H), 2.63 (m, 2H), 1.66 (m, 2H). 319.0 K-10

39 8.23 (s, 1H), 7.58 (brs, 1H), 3.33 (m, 2H), 3.31 (m, 2H), 3.25 (m,2H), 2.22 (m, 2H), 1.71 (m, 6H). 347.1 K-11

56 8.23 (s, 1H), 7.72 (brs, 1H), 4.16 (m, 2H), 3.36 (m, 2H), 3.28 (m,4H), 1.95 (m, 2H), 1.76 (m, 2H). 349.0 K-12

48 8.23 (s, 1H), 7.72 (m, 1H), 4.11 (s, 2H), 3.76 (m, 2H), 3.49 (m, 2H),3.33 (m, 4H), 1.83 (m, 2H), 1.71 (m, 2H). 363.0 K-13

50 8.23 (s, 1H), 7.74 (brs, 1H), 3.66 (brs, 4H), 3.48 (m, 2H), 3.34 (m,4H), 2.63 (m, 2H), 1.67 (m, 2H). 363.2 J-1

100 7.53 (t, J = 5.7 Hz, 1H), 3.40 (q, J = 6.5 Hz, 2H), 3.34 (t, J = 7.0Hz, 2H), 3.19 (t, J = 6.8 Hz, 2H), 2.46 (s, 3H), 2.21 (t, J = 8.1 Hz,2H), 1.91 (p, J = 7.5 Hz, 2H), 1.71 (m, 2H). 335.2 J-2

91 8.24 (s, 1H), 7.58 (t, J = 5.8 Hz, 1H), 3.40 (q, J = 6.5 Hz, 2H),3.21-3.28 (m, 4 H), 2.46 (s, 3H), 2.21 (t, J = 6.2 Hz, 2H), 1.65- 1.75(m, 6H). 349.2 J-3

65 8.25 (d, J = 1.1 Hz, 1H), 7.51 (t, J = 5.8 Hz, 1H), 4.15 (t, J = 5.3Hz, 2H), 3.44 (q, J = 6.6 Hz, 2H), 3.22-3.27 (m, 4H), 2.46 (s, 3H),1.89-1.95 (m, 2H), 1.73- 1.80 (m, 2H). 351.2 J-4

77 8.25 (s, 1H), 1.54 (t, J = 5.2 Hz, 1H), 4.02 (s, 2H), 3.82 (t, J =5.2 Hz, 2H), 3.44 (q, 2H), 3.34 (m, 4H), 2.47 (s, 3H), 1.77 (m, 2H).351.1 J-5

65 8.26 (s, 1H), 7.53 (m, 1H), 3.45 (m, 2H), 3.34 (m, 4H), 2.48 (s, 3H),2.43 (m, 2H), 1.66 (m, 4H), 1.52 (m, 4H). 363.2 J-6

64 8.25 (s, 1H), 7.52 (brs, 1H), 4.11 (s, 2H), 3.75 (t, J = 5.6 Hz, 2H),3.48 (m, 2H), 3.45 (m, 2H), 3.34 (m, 2H), 2.47 (s, 3H), 1.82 (m, 2H),1.72 (m, 2H). 365.3 J-7

47 8.25 (s, 1H), 7.52 (bs, 1H), 3.64 (m, 4H), 3.47 (m, 2H), 3.42 (m,2H), 3.32 (m, 2H), 2.63 (t, J = 4.8 Hz, 2H), 2.47 (s, 3H), 1.68 (m, 2H).365.3 J-8

89 8.25 (s, 1H), 7.51 (t, J = 5.8 Hz, 1H), 3.64 (m, 4H), 3.46 (m, 2H),3.42 (q, J = 6.5 Hz, 2H), 3.31 (m, 2H), 2.62 (m, 2H), 2.46 (s, 3H), 1.68(m, 2H). 322.2 J-A

81 8.26 (s, 1H), 7.53 (t, J = 5.7 Hz, 1H), 3.39 (m, 2H), 3.09 (m, 2H),3.06 (s, 2H), 2.46 (s, 3H), 1.74 (m, 2H), 1.17 (s, 6H). 349.2 J-B

crude No NMR Data 379.2 J-C

crude No NMR Data 393.2

General Method of Pd Coupling Reaction Intermediate M-1:4-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one

A solution of 1-(3-aminopropyl) piperidin-2-one hydrochloride (H-III-1,9.0 g, 29.3 mmol) and 2-chloro-4-iodo-5-(trifluoromethyl) pyridine (6.19g, 32.2 mmol) in toluene (180 mL) was treated with cesium carbonate(23.9 g, 73.2 mmol). The mixture was purged with Ar for 15 min. Then,PdCl₂(dppf) DCM (2.39 g, 2.93 mmol) was added and the mixture was purgedwith Ar for a further 5 min. The seal tube was closed and conventionallyheated in a pre-heated oil bath at 90° C. for 16 h. The reaction mixturewas cooled to rt, poured into water (100 mL). The solution was extractedwith EtOAc (3×100 mL). The combined organic extracts were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (40 to 45% EtOAc/hexane, 12 CV's) to obtain1-(3-((2-chloro-5-(trifluoromethyl) pyridin-4-yl) amino) propyl)piperidin-2-one (2.6 g, 26% yield) as brown solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.18 (s, 1H), 6.98 (t, J=6 Hz, 1H), 6.88 (s, 1H), 3.29 (m,2H), 3.15 (m, 4H), 2.22 (t, J=6.4 Hz, 2H), 1.67 (m, 6H); LC-MS (ESI)m/z: 336.1 (M+H⁺).

Using the General Method for preparation of Intermediate M-1, thefollowing intermediates of Table G were prepared.

TABLE G LC-MS Yield (m/z: Intermediate Structure (%) ¹H NMR (400 MHz,DMSO-d₆): δ (M + H⁺) M-2

26 8.18 (s, 1H), 6.90 (s, 1H), 6.87 (brs, 1H), 4.16 (m, 2H), 3.25 (m,6H), 1.92 (m, 2H), 1.72 (m, 2H). 338.2 M-3

27 8.18 (s, 1H), 6.90 (brs, 2H), 3.64 (brs, 4H), 3.48 (m, 2H), 3.26 (m,4H), 2.63 (m, 2H), 1.63 (m, 2H). 351.1 M-4

19 7.99 (s, 1H), 6.75 (s, 2H), 3.62 (m, 4H), 3.49 (m, 2H), 3.35 (m, 2H),3.20 (m, 2H), 2.94 (brs, 2H), 1.65 (m, 2H). 318.2

General Method of Oxidation to Sulfinyl Intermediates Intermediate J-14:4-(3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one

A solution of4-(3-((2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one(J-7, 3.0 g, 8.2 mmol) in DCM (60 mL) at 0° C., m-CPBA (2.0 g, 11.5mmol) was added and stirred from 0° C. to room temperature for 3 h. Thereaction mixture was washed with saturated aq. sodium bicarbonate (2×90mL). Organic layer was dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated under reduced pressure to obtain mixture of4-(3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-oneand4-(3-((2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one(3.0 g, 95%, 9:1) as light yellow semi-solid. ¹H NMR (400 MHz, DMSO-d₆):δ 8.59 (s, 1H), 7.94 (brs, 1H), 3.60 (m, 4H), 3.45 (m, 4H), 3.36 (m,2H), 2.88 (s, 3H), 2.63 (m, 2H), 1.70 (m, 2H); LC-MS (ESI) m/z: 381.3(M+H⁺).

Using the General Method for preparation of Intermediate J-14, thefollowing intermediates of Table H were prepared.

TABLE H LC-MS Yield (m/z: Intermediate Structure (%) ¹H NMR (400 MHz,DMSO-d₆): δ (M + H⁺) J-8-A

90 8.58 (s, 1H), 8.01 (s, 1H), 3.46 (m, 2H), 3.35 (m, 2H), 3.20 (m, 2H),2.83 (s, 3H), 2.22 (m, 2H), 1.96 (m, 2H), 1.71 (m, 2H). 351.2 J-9

96 8.58 (s, 1H), 8.06 (s, 1H), 3.46 (m, 2H), 3.35 (m, 2H), 3.24 (m, 2H),2.72 (s, 3H), 2.23 (m, 2H), 1.73 (m, 6H). 365.3 J-10

92 8.58 (s, 1H), 7.99 (brs, 1H), 4.16 (m, 2H), 3.48 (m, 2H), 3.26 (m,4H), 2.83 (s, 3H), 1.92 (m, 2H), 1.78 (m, 2H). 367.2 J-11

96 8.59 (s, 1H), 8.00 (brs, 1H), 4.03 (s, 2H), 3.84 (m, 2H), 3.48 (m,2H), 3.35 (m, 4H), 2.84 (s, 3H), 1.79 (m, 2H). 367.1 J-12

83 8.58 (s, 1H), 8.02 (brs, 1H), 3.45 (m, 2H), 3.34 (m, 4H), 2.83 (s,3H), 2.43 (m, 2H), 1.69 (m, 4H), 1.56 (m, 4H). 379.4 J-13

96 8.58 (s, 1H), 7.98 (s, 1H), 4.12 (s, 2H), 3.74 (m, 2H), 3.48 (m, 4H),3.34 (m, 2H), 2.83 (s, 3H), 1.77 (m, 2H), 1.73 (m, 2H). 381.3 J-14

95 8.59 (s, 1H), 7.94 (brs, 1H), 3.60 (m, 4H), 3.45 (m, 4H), 3.36 (m,2H), 2.88 (s, 3H), 2.63 (m, 2H), 1.70 (m, 2H). 381.3 J-15

100 No NMR Data 338.2 J-16

crude No NMR Data 365.2 J-17

crude No NMR Data 395.2 J-18

crude No NMR Data 409.2

Exemplary Compounds:

Using the methods described above the following compounds of Formula I-Aand Formula I-B were prepared. Exemplary compounds of Formula I-A andFormula I-B are shown below in Table I. Exemplary methods for thepreparation of the compounds are also provided below.

General Method I: Substitution Reaction Example 23:1-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one

A solution of1-(3-((5-bromo-2-chloropyrimidin-4-yl)amino)propyl)piperidin-2-one(K-10, 4.0 g, 11.6 mmol) in 2-butanol (80 mL) at rt was treated with2-ethyl-4-(4-methylpiperazin-1-yl)aniline (D-I-11, 2.53 g, 11.6 mmol).The reaction mixture was treated with 4N HCl in 1,4-dioxane (3.5 mL,13.9 mmol) and stirred at 95° C. for 72 h. The reaction mixture wascooled to rt and then basified with sat′ d aqueous NaHCO₃. The solutionwas extracted with DCM (3×50 mL) and the combined organics were driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The crude was purified silica gel column chromatography (4 to 5%MeOH/DCM, 10 CV's). The product was dissolved in DCM (200 mL) and addedQuadraSil-MP resin (w/w) in order to remove residual palladium. Thesolution was stirred for 4 h and filtered. The filtrate was evaporatedto obtain1-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one(1.70 g, 28% yield) as off white solid. ¹H NMR (400 MHz, DMSO-d₆): δ8.09 (s, 1H), 7.81 (s, 1H), 7.13 (d, J=8.5 Hz, 1H), 6.80 (m, 1H), 6.74(m, 1H), 6.71 (m, 1H), 3.21 (m, 4H), 3.14 (m, 2H), 3.07 (m, 5H), 2.43(m, 5H), 2.21 (s, 5H), 1.67 (s, 4H), 1.61 (m, 2H), 1.05 (t, J=7.4 Hz,3H); LC-MS (ESI) m/z: 530.3 (M+H⁺).

General Method J: Substitution Reaction tert-butyl4-(4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1,4-diazepane-1-carboxyl

A solution of tert-butyl 4-(4-aminophenyl)-1,4-diazepane-1-carboxylate(D-I-12, 0.21 g, 0.57 mmol) and1-(3-((2-(methylsulfinyl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one(J-9, 0.17 g, 0.57 mmol) in DMF (3.0 mL) was sealed and heated at 90° C.for 12 h. The mixture was concentrated and the crude was purified bysilica gel column chromatography (0 to 4% MeOH/DCM, 12 CV's) to provideproduct tert-butyl4-(4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1,4-diazepane-1-carboxylate(0.20 g, 60% yield). LC-MS (ESI) m/z: 592.4 (M+H⁺).

General Method K: Deprotection of Boc Group of R⁴ Moieties Example 9:1-(3-((2-((4-(1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one

A solution of tert-butyl4-(4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1,4-diazepane-1-carboxylate(0.20 g, 0.34 mmol) in DCM (3 mL) was treated with 4 N HCl in1,4-dioxane (1.0 mL). The mixture was stirred at rt for 2 h. Thesolution was concentrated and the residue was dissolved in water (1.0mL) and acetonitrile (1 mL), frozen and lyophilized to obtain1-(3-((2-((4-(1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-onehydrochloride (0.12 g, 67% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.23(brs, 1H), 8.27 (s, 1H, FA), 8.08 (s, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.06(s, 1H), 6.67 (d, J=8.5 Hz, 2H), 3.51 (t, J=5.0 Hz, 2H), 3.47 (t, J=6.2Hz, 3H), 3.34-3.37 (m, 3H), 3.30 (t, J=6.9 Hz, 3H), 3.20 (s, 3H), 2.98(t, J=4.9 Hz, 2H), 2.80 (t, J=5.6 Hz, 2H), 2.21 (t, J=6.0 Hz, 2H),1.87-1.90 (m, 2H), 1.69-1.75 (m, 7H); LC-MS (ESI) m/z: 492.4 (M+H⁺).

General Method L: Reductive Alkylation of R⁴ Moieties Example 10:1-(3-((2-((4-(4-ethyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one

A solution of1-(3-((2-((4-(1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one(9, 0.10 g, 0.20 mmol)) in methanol (0.5 mL) was treated withacetaldehyde (0.1 mL 1.8 mmol), and acetic acid (2 drops). Sodiumcyanoborohydride (0.026 g, 0.41 mmol) was added and the mixture wasstirred at rt 6 h. The solution was treated with brine and thenextracted with EtOAc (3×15 mL). The combined organics were dried overanhydrous Na₂SO₄, filtered and concentrated. The crude was purified byreverse-phase column chromatography (0% to 20% CH₃CN/H₂O (0.1% FA), 15CV's) to obtain1-(3-((2-((4-(4-ethyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one(56 mg, 49% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.21 (brs, 1H), 8.17(s, 1H, FA), 8.08 (s, 1H), 7.45 (d, J=8.3 Hz, 2H), 7.05 (s, 1H), 6.63(d, J=8.7 Hz, 2H), 3.47 (t, J=4.9 Hz, 3H), 3.36-3.42 (m, 5H), 3.30 (t,J=6.9 Hz, 3H), 3.19 (s, 3H), 2.72 (t, J=4.7 Hz, 2H), 2.53-2.56 (m, 4H),2.21 (t, J=5.9 Hz, 2H), 1.83-1.88 (m, 2H), 1.68-1.73 (m, 7H), 0.98 (t,J=7.1 Hz, 3H); MS (ESI) m/z: 520.4 (M+H⁺).

General Method of Acylation of R⁴ Moieties Example 36:1-(3-((2-((4-(4-acetylpiperazin-1-yl)-2-cyclopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one

A solution of1-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one(34, 0.21 g, 0.40 mmol) in 2.5 mL of 30% MeCN: water was treated withacetic anhydride (1.0 eq) at rt. The reaction mixture was stirred at rtfor 30 min and the solution was diluted with water (15 mL). The solutionwas extracted with EtOAc (3×20 mL) and the combined organics were washedwith sat′ d NaHCO₃ (15 mL). The organic layer was dried with MgSO₄,filtered and concentrated under reduced pressure. The crude was purifiedby silica gel column chromatography (0 to 10% DCM/MeOH, 25CV) to yield1-(3-((2-((4-(4-acetylpiperazin-1-yl)-2-cyclopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one(0.13 g, 57% yield) as a clear glassy solid. ¹H NMR (400 MHz, DMSO-d₆):δ 8.64 (brs, 1H), 8.04 (s, 1H), 7.27 (s, 1H), 7.05 (brs, 1H), 6.75 (d,1H), 6.46 (s, 1H), 3.54 (d, 4H), 3.01-3.24 (m, 10H), 2.18-2.19 (m, 2H),2.02 (s, 3H), 1.91-1.96 (m, 1H), 1.61-1.67 (m, 6H), 0.82 (d, 2H), 0.58(d, 2H); LC-MS (ESI) m/z: 560.4 (M+H⁺).

General Method M: Pd Coupling Reaction Example 97:1-(3-((2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one

A mixture of commercially available5-(4-methylpiperazin-1-yl)pyridin-2-amine (0.13 g, 0.66 mmol) and1-(3-((2-chloro-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one(M-1, 0.20 g, 0.60 mmol) in 1,4-dioxane (3 mL) was treated with cesiumcarbonate (0.39 g, 1.2 mmol). The solution was sparged with Ar andtreated with Pd₂(dba)₃ (0.055 g, 0.06 mmol) and Xantphos (0.069 g, 0.12mmol). The mixture was sparged again with Ar, capped tightly and heatedat 90° C. 15 h. The mixture was cooled to rt, diluted with DCM (20 mL)and water (10 mL). The black solid was filtered off and then thefiltrate was treated with brine. The solution was extracted withadditional DCM (3×25 mL). The combined organics were dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toobtain1-(3-((2-((5-(4-methylpiperazin-1-yl)pyridin-2-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one(0.18 g, 57% yield) as an orange solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.35 (s, 1H), 8.01 (s, 1H), 7.90 (d, J=3.0 Hz, 1H), 7.55 (d, J=9.1 Hz,1H), 7.37 (dd, J=9.1 and 3.1 Hz, 1H), 7.11 (s, 1H), 6.19-6.21 (m, 1H),3.31-3.35 (m, 2H), 3.22-3.26 (m, 2H), 3.13 (q, J=6.5 Hz, 2H), 3.05-3.10(m, 4H), 2.44-2.49 (m, 4H), 2.20-2.23 (m, 5H), 1.66-1.76 (m, 6H); LC-MS(ESI) m/z: 492.2 (M+H⁺).

TABLE I Exemplary compounds. LC-MS Example Yield ¹H NMR (400 MHz, DMSO-(m/z: Number Product Method (%) d₆): δ (M + H⁺) 1

I 20 8.58 (1H, s), 8.14 (s, 1H), 7.56 (m, 3H), 6.89 (t, J = 6.0 Hz, 1H),6.81 (d, J = 8.7 Hz, 2H), 3.43 (m, 2H), 3.16 (t, 2H, J = 7.2 Hz), 2.96(d, J = 5.3 Hz, 4H), 2.65 (t, J = 4.8 Hz, 4H), 2.26 (t, J = 7.8 Hz, 2H),1.77 (t, J = 7.8 Hz, 2H), 1.72 (m, 2H), 1.63 (m, 1H), 1.43 (m, 1H), 1.16(s, 6H), 0.80 (m, 2H), 0.43 (m, 4H), 0.32 (m, 2H). 504.4 2

J 20 8.32 (s, 1H), 8.03 (s, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.77 (brs,1H), 6.74 (m, 1H), 6.63 (m, 1H), 3.26 (m, 4H), 3.13 (m, 6H), 2.56 (brs,4H), 2.31 (s, 3H), 2.20 (m, 2H), 2.16 (s, 3H), 1.90 (m, 2H), 1.64 (m,2H). 492.4 3

J 22 9.72 (s, 1H), 9.24 (brs, 1H), 8.26 (s, 1H), 7.89 (brs, 1H), 7.32(d, J = 8.6 Hz, 1H), 6.91 (brs, 1H), 6.86 (dd, J = 2.4, 8.7 Hz, 1H),3.41 (m, 4H), 3.32 (m, 2H), 3.27 (m, 2H), 3.21 (brs, 4H), 3.12 (m, 2H),2.23 (s, 3H), 2.20 (m, 2H), 1.90 (m, 2H), 1.67 (m, 2H). 478.4 4

J 64 8.60 (brs, 1H), 8.02 (brs, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.86 (m,1H), 6.76 (brs, 1H), 6.72 (dd, J = 2.5 and 8.5 Hz, 1H), 3.21 (brs, 4H),3.09 (brs, 6H), 2.49 (m, 2H), 2.44 (m, 4H), 2.19 (m, 5H), 1.87 (m, 2H),1.57 (brs, 2H), 1.05 (t, J = 7.4 Hz, 3H). 506.4 5

I & K 47 8.32 (s, 1H, FA), 8.20 (s, 1H), 7.80 (s, 1H), 7.44 (d, J = 8.2Hz, 1H), 7.06 (t, J = 6.1 Hz, 1H), 7.00 (s, 1H), 6.97 (m, 1H), 3.24-3.32(m, 6H), 3.18 (m, 2H), 2.90 (m, 2H), 2.71 (m 2H), 2.20 (m, 2H), 2.18 (s,3H), 1.86 (m, 2H), 1.76 (m, 2H), 1.67 (m, 6H). 457.4 6

I 65 8.20 (brs, 1H, FA), 8.16 (s, 1H), 7.79 (s, 1H), 7.40 (d, J = 8.2Hz, 1H), 7.04 (t, J = 6.1 Hz, 1H), 7.01 (s, 1H), 6.98 (m, 1H), 3.24-3.30(m, 4H), 3.17 (m, 2H), 2.98 (m, 2H), 2.43 (m, 1H), 2.29 (m, 3H),2.13-2.20 (m, 4H), 2.17 (s, 3H), 1.6-1.8 (m, 10H). 471.4 7

J & K 80 8.74 (s, 1H), 8.32 (s, 1H, FA), 8.06 (s, 1H), 7.36 (d, J = 8.0Hz, 1H), 6.9-7.1 (m, 2H), 3.19-3.32 (m, 6H), 3.15 (m, 2H), 2.90 (m, 2H),2.73 (m, 1H), 2.18 (s, 3H), 2.18-2.20 (m, 2H), 2.18 (s, 3H), 1.86 (m,2H), 1.76 (m, 2H), 1.60-1.70 (m, 6H). 491.4 8

J 42 8.71 (s, 1H), 8.20 (s, 1H, FA), 8.05 (s, 1H), 7.33 (d, J = 8.1 Hz,1H), 7.04 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 7.00 (m, 1H), 3.19-3.25 (m,4H), 3.15 (m, 2H), 2.97 (m, 2H), 2.44 (m, 1H), 2.29 (s, 3H), 2.1-2.2 (m,4H), 2.17 (s, 3H), 1.6-1.8 (m, 10H). 505.4 11

J 7 8.60 (s, 1H), 8.34 (s, 1H: FA), 8.01 (s, 1H), 7.10 (m, 1H), 6.95 (m,1H), 6.76 (s, 1H), 6.70 (m 1H), 3.1-3.4 (brm, 6H), 3.09 (m, 2H), 2.50(m, 3H), 2.44 (m, 5H), 2.21 (s, 3H), 2.20 (m, 2H), 1.65 (brm, 4H), 1.54(brm, 2H), 1.06 (t, J = 7.4 Hz, 3H). 520.4 12

J, K & L 5 8.60 (brs, 1H), 8.01 (brs, 1H), 7.10 (brm, 1H), 6.95 (t, 1H,J = 5.8 Hz), 6.76 (m, 1H), 6.72 (m, 1H), 3.19 (brs, 4H), 3.05-3.10 (m,6H), 2.50 (m, 4H), 2.48 (m, 6H), 2.33-2.37 (m, 2H), 2.18 (m, 2H), 1.66(brm, 4H), 1.58 (brm, 2H), 1.06 (t, J = 7.4 Hz, 3H), 1.01 (t, J = 7.2Hz, 3H). 534.4 13

J, K & L 20 8.57 (s, 1H), 8.03 (s, 1H), 7.24 (brm, 1H), 6.98 (d, J = 6.3Hz, 1H), 6.71 (d, J = 8.9 Hz, 1H), 6.43 (s, 1H), 3.22 (brm, 4H), 3.12(brm, 2H), 3.09 (brm, 4H), 2.41 (brm, 4H), 2.35 (brm, 3H), 2.18- 2.19(m, 2H), 1.93 (m, 1H), 1.66 (brm, 4H), 1.60 (brm, 2H), 1.02 (brm, 3H),0.81 (m, 2H), 0.57 (m, 2H). 546.4 14

J 29 8.57 (s, 1H), 8.17 (s, 1H, FA), 8.03 (s, 1H), 7.24 (brm, 1H), 6.98(m, 1H), 6.71 (m, 1H), 6.42 (d, J = 2.7 Hz, 1H), 3.12-3.24 (m, 10H),3.06 (t, J = 4.8 Hz, 4H), 2.43 (m, 4H), 2.18- 2.20 (m, 5H), 1.94 (m,1H), 1.66 (brm, 4H), 1.60 (brm, 2H), 0.81 (m, 2H), 0.56 (m, 2H). 578.415

I 6 8.10 (s, 1H), 7.79 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.78 (m, 2H),6.70 (dd, J = 2.2 and 8.6 Hz, 1H), 3.19 (m, 4H), 3.09 (m, 7H), 2.45(brs, 4H), 2.21 (s, 3H), 2.19 (m, 2H), 1.67 (brs, 4H), 1.59 (m, 2H),1.09 (d, J = 6.8 Hz, 6H). 544.4 546.4 16

J 68 10.18 (brs, 1H), 9.26 (brs, 2H), 8.50 (brs, 1H), 7.32 (t, J = 8.56Hz, 1H), 6.94 (s, 1H), 6.89 (d, J = 8.56 Hz, 1H), 3.38 (brs, 4H), 3.20(brs, 10H), 2.21 (brs, 5H), 1.63 (brs, 6H). 492.4 17

J, K & L 26 8.62 (s, 1H), 8.03 (s, 1H), 7.17 (brs, 1H), 6.98 (s, 1H),6.75 (m, 2H), 3.21 (brs, 4H), 3.14 (brs, 2H), 3.06 (brm, 4H), 2.55 (m,2H), 2.20 (brm, 2H), 2.14 (s, 3H), 1.63 (m, 7H), 1.19 (brm, 2H), 1.00(brm, 6H). 534.5 18

J 43 8.60 (s, 1H), 8.02 (s, 1H), 7.13-7.20 (m, 1H), 6.97 (t, J = 5.8 Hz,1H), 6.77 (s, 1H), 6.72 (d, J = 8.9 Hz, 1H), 4.61 (t, J = 4.9 Hz, 1H),4.51 (t, J = 4.9 Hz, 1H), 3.11-3.25 (m, 6H), 3.06- 3.10 (m, 4H), 2.68(t, J = 4.9 Hz, 1H), 2.62 (t, J = 4.9 Hz, 1H), 2.57 (t, J = 4.7 Hz, 4H),2.19-2.20 (m, 2H), 2.13 (s, 3H), 1.59-1.66 (m, 6H). 538.4 19

J, K & L 26 8.61 (s, 1H), 8.03 (s, 1H), 7.16 (d, J = 7.0 Hz, 1H), 6.98(brs, 1H), 6.76 (s, 1H), 6.72 (d, J = 8.4 Hz, 1H), 3.20 (brs, 4H), 3.14(brs, 2H), 3.08 (brs, 4H), 2.49 (m, 4H), 2.34 (m, 2H), 2.19 (brs, 2H),2.13 (s, 3H), 1.63 (m, 6H), 1.02 (t, J = 7.0 Hz, 3H). 520.5 20

J 30 8.60 (s, 1H), 8.03 (s, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.96 (brs,1H), 6.77 (s, 1H), 6.72 (d, J = 8.6 Hz, 1H), 3.20 (brs, 4H), 3.14 (brs,2H), 3.08 (brs, 4H), 2.43 (brs, 4H), 2.20 (brs, 5H), 2.13 (s, 3H), 1.63(m, 6H). 506.4 21

J, K & L 12 8.30 (s, 1H), 8.03 (s, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.76(s, 1H), 6.71 (m, 2H), 3.27 (m, 4H), 3.15 (m, 2H), 3.10 (brs, 4H), 2.81(m, 1H), 2.41 (brs, 4H), 2.20 (m, 2H), 2.16 (s, 3H), 2.00 (m, 2H), 1.85(m, 2H), 1.66 (m, 8H). 546.5 22

J, K & L 19 8.61 (s, 1H), 8.02 (s, 1H), 7.15 (brs, 1H), 6.97 (brs, 1H),6.76 (s, 1H), 6.71 (d, J = 7.8 Hz, 1H), 3.21 (m, 5H), 3.04 (brs, 4H),2.65 (brs, 4H), 2.19 (brs, 2H), 2.13 (s, 3H), 1.67 (m, 8H), 0.42 (m,2H), 0.33 (m, 2H). 532.4 24

J 16 8.52 (s, 1H), 8.02 (s, 1H), 7.11 (brs, 1H), 6.96 (s, 1H) 6.47 (d, J= 6.8 Hz, 1H), 6.13 (s, 1H), 3.46 (brs, 2H), 3.37 (m, 2H), 3.17 (m, 8H),2.58 (brs, 2H), 2.43 (brs, 2H), 2.25 (s, 3H), 2.19 (s, 2H), 1.87 (m,1H), 1.58 (m, 6H), 0.79 (m, 2H), 0.54 (m, 2H). 546.6 25

J 72 8.67 (brs, 1H), 8.12 (s, 1H, FA), 8.03 (brs, 1H), 7.23 (d, J = 8.6Hz, 1H), 6.91 (brm, 1H), 6.84 (s, 1H), 6.79 (d, J = 8.9 Hz, 1H), 4.13(t, J = 5.2 Hz, 2H), 3.10-3.40 (m, 14H), 2.76 (brs, 3H), 2.15 (s, 3H),1.87-1.92 (m, 2H), 1.62-1.69 (brm, 2H). 508.2 26

I 6 8.02 (s, 1H), 7.85 (s, 1H), 7.35 (d, J = 8.72 Hz, 1H), 6.86 (t, J =5.76 1H), 6.71 (dd, J = 2.5 and 8.7 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H),3.25 (m, 4H), 3.15 (m, 2H), 3.05 (brs, 4H), 2.44 (brs, 4H), 2.20 (m,5H), 1.94 (m, 1H), 1.65 (m, 6H), 0.82 (m, 2H), 0.56 (m, 2H). 544.3 546.327

I 13 8.02 (s, 1H), 7.78 (s, 1H), 7.35 (d, J = 8.72 Hz, 1H), 7.03 (t,1H), 6.70 (dd, J = 2.5 and 8.8 Hz, 1H), 6.44 (d, J = 2.44 Hz, 1H), 3.24(m, 4H), 3.15 (m, 2H), 3.04 (brs, 4H), 2.42 (brs, 4H), 2.42 (m, 5H),1.94 (m, 1H), 1.66 (m, 6H), 0.82 (m, 2H), 0.56 (m, 2H). 498.4 28

J 18 8.30 (s, 1H), 8.01 (s, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.80 (d, J =2.6 Hz, 1H) 6.72 (dd, J = 2.6 and 8.6 Hz, 1H), 6.66 (m, 1H), 3.23 (m,4H), 3.12 (brs, 8H), 2.50 (m, 3H), 2.39 (m, 2H), 2.19 (m, 2H), 1.69 (t,J = 3.4 Hz, 4H), 1.59 (t, J = 6.8 Hz, 2H), 1.13 (d, J = 6.8 Hz, 6H),1.04 (t, J = 7.1 Hz, 3H). 548.5 29

I 10 8.08 (s, 1H), 7.72 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.94 (t, J =5.7 Hz, 1H), 6.78 (d, J = 2.4 Hz, 1H), 6.69 (dd, J = 2.4 and 8.6 Hz,1H), 3.16 (m, 14H), 2.35 (m, 2H), 2.19 (d, J = 5.8 Hz, 2H), 1.8 (m, 1H),1.62 (m, 6H), 1.09 (d, J = 6.8 Hz, 6H), 1.03 (t, J = 7.1 Hz, 3H). 514.530

I 9 8.09 (s, 1H), 7.79 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.78 (brs,2H), 6.67 (dd, J = 8.5 and 16.6 Hz, 1H), 3.15 (m, 14H), 2.47 (m, 1H),2.36 (q, 2H), 2.19 (brs, 2H), 1.62 (m, 6H), 1.09 (d, J = 6.8 Hz, 6H),1.03 (t, J = 7.0 Hz, 3H). 558.4 560.4 31

J, K & L 6 8.24 (brs, 1H), 8.00 (s, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.69(brs, 1H), 6.53 (s, 1H), 6.50 (m, 1H), 3.50 (m, 2H), 3.43 (m, 2H), 3.23(m, 4H), 3.09 (m, 4H), 2.68 (m, 2H), 2.53 (m, 2H), 2.31 (s, 3H), 2.20(m, 2H), 1.91 (m, 2H), 1.64 (m, 6H), 1.08 (t, J = 7.4 Hz, 3H). 534.4 32

I 50 11.4 (brs, 1H), 10.10 (s, 1H), 8.75 (s, 1H), 8.19 (brs, 1H), 7.30(brs, 1H), 6.86- 6.90 (m, 2H), 3.81 (d, J = 11.3 Hz, 2H), 3.43 (d, J =10.4 Hz, 2H), 3.2-3.05 (m, 10 H), 2.75 (d, J = 4.4 Hz, 3H), 2.54 (d, J =8.6 Hz, 2H), 2.15 (s, 2H), 1.63 (s, 6 H), 1.08 (t, J = 7.5 Hz, 3H).486.2 33

J 11 8.30 (s, 1H), 8.01 (s, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.80 (d, J =2.4 Hz, 1H), 6.72 (dd, J = 2.5 and 8.6 Hz, 1H), 6.66 (brs, 1H), 3.24 (m,5H), 3.14 (m, 8H), 2.50 (m, 2H), 2.25 (s, 3H), 2.20 (m, 2H), 1.69 (m,4H), 1.61 (m, 2H), 1.13 (d, J = 6.8 Hz, 6H). 534.5 34

I & K 49 8.59 (s, 1H), 8.03 (s, 1H), 7.25 (s, 1H), 6.99 (s, 1H), 6.72(d, J = 8.9 Hz, 1H), 6.43 (s, 1H), 3.10-3.25 (m, 7H), 3.06 (t, 4H), 2.93(m, 4H), 2.18 (m, 2H), 1.91- 1.95 (m, 1H), 1.59-1.70 (m, 6H), 0.81 (m,2H), 0.57 (m, 2H). 518.2 35

I 39 8.63 (s, 1H), 8.11 (s, 1H), 7.45 (d, J = 14.4 Hz, 1H), 7.15 (s,1H), 6.55 (d, J = 9.6 Hz, 1H), 3.28 (s, 1H), 3.22 (m, 2H), 3.15 (s, 3H),3.01 (brs, 4H), 2.19 (m, 2H), 1.92-1.98 (m, 1H), 1.66 (m, 6 H), 0.85 (m,2H), 0.57 (m, 2H). 550.2 37

J & K 48 10.3 (brs, 1H), 9.37 (brs, 1H), 8.49 (brs, 1H), 7.37 (brs, 1H),6.94 (s, 1H), 6.89 (d, J = 9.0 Hz, 1H), 4.09- 4.15 (m, 2H), 3.55 (brs,4H), 3.35-3.42 (m, 4H), 3.08-3.23 (m, 6H), 2.22 (s, 3H), 1.85-1.92 (m,2H), 1.62-1.73 (brm, 2H). 494.2 38

J 30 8.60 (s, 1H), 8.04 (s, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.98 (d, J =5.6 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.44 (d, J = 2.0 Hz, 1H), 3.23(brs, 6H), 3.12 (brs, 4H), 2.59 (brs, 4H), 2.39 (d, J = 9.6 Hz, 2H),2.33 (brs, 3H), 1.94 (m, 1H), 1.58 (m, 8H), 0.81 (m, 2H), 0.59 (m, 2H).546.5 39

J 29 8.67 (s, 1H), 8.02 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.89 (s, 1H),6.76-6.81 (m, 2H), 4.12 (t, J = 5.2 Hz, 2H), 3.25-3.38 (m, 7H), 3.13(brs, 4H), 2.97 (brs, 4H), 2.51-2.59 (m, 4H), 1.88 (t, J = 6.1 Hz, 2H),1.63 (brs, 2H), 1.06 (t, J = 7.5 Hz, 3H). 522.4 40

I 12 8.05 (s, 1H), 7.86 (s, 1H), 7.34 (d, J = 8.5 Hz, 1H), 6.82 (m, 1H),6.71 (d, J = 8.2 Hz, 1H), 6.44 (s, 1H), 4.12 (s, 2H), 3.27 (m, 2H), 3.17(brs, 4H), 3.04 (brs, 4H), 2.42 (brs, 4H), 2.20 (s, 3H), 1.91 m, 2H),1.69 (brs, 2H), 1.03 (m, 1H), 0.82 (m, 2H), 0.57 (m, 2H). 544.5 41

J 13 8.25 (s, 1H), 8.05 (s, 1H), 7.34 (d, J = 8.7 Hz, 1H), 6.73 (dd, J =2.6 and 8.7 Hz, 1H), 6.65 (brs, 1H), 6.49 (d, J = 2.5 Hz, 1H), 4.13 (t,J = 5.2 Hz, 2H), 3.33 (q, J = 6.4 Hz, 2H), 3.19 (m, 4H), 3.09 (m, 4H),2.45 (m, 4H), 2.23 (s, 3H), 1.92 (m, 3H), 1.71 (m, 2H), 0.84 (m, 2H),0.59 (m, 2H). 534.2 41

J 44 10.6 (brs, 1H), 7.32 (brs, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.54 (s,1H), 4.12 (s, 2H), 3.79-3.82 (m, 2H), 3.48-3.45 (m, 2H), 3.30 (brs, 2H),2.99-3.14 (m, 8H), 2.80 (s, 3H), 1.87-1.94 (m, 4H), 1.68 (brs, 1H), 0.87(m, 2H), 0.65 (m, 2H). 534.2 42

J 6 8.58 (s, 1H), 8.04 (s, 1H), 7.23 (s, 1H), 6.90 (s, 1H), 6.73 (dd, J= 8.8 and 2.7 Hz, 1H), 6.43 (d, J = 2.7 Hz, 1H), 4.11 (m, 2H), 3.69 (m,1H), 3.55 (m, 1H), 3.29 (m, 1H), 3.13 (s, 4H), 3.02 (d, 2H), 2.66 (m,1H), 2.32 (m, 1H), 2.20 (m, 1H), 1.70- 2.07 (brm, 11H), 1.35 (m, 1H),0.81 (m, 2H), 0.57 (m, 2H). 560.3 43

I 7 8.08 (s, 1H), 7.74 (s, 1H), 7.13 (d, J = 8.5 Hz, 1H), 6.92 (m, 1H),6.74 (d, J = 2.3 Hz, 1H), 6.71 (dd, J = 2.5 and 8.6 Hz, 1H), 4.12 (t, J= 5.1 Hz, 2H), 3.25 (m, 2H), 3.16 (m, 4H), 3.07 (m, 4H), 2.52 (m, 2H),2.43 (m, 4H), 2.21 (s, 3H), 1.88 (m, 2H), 1.67 (m, 2H), 1.05 (t, J = 7.2Hz, 3H). 488.2 44

I 9 7.83 (s, 1H), 7.74 (s, 1H), 7.20 (d, J = 8.6 Hz, 1H), 6.75 (d, J =2.6 Hz, 1H), 6.71 (dd, J = 2.7 and 8.6 Hz, 1H), 6.49 (m, 1H), 4.14 (t, J= 5.3 Hz, 2H), 3.29 (m, 2H), 3.21 (m, 4H), 3.11 (m, 4H), 2.56 (m, 2H),2.46 (m, 4H), 2.24 (s, 3H), 1.93 (m, 2H), 1.71 (m, 2H), 1.10 (t, J = 7.5Hz, 3H). 532.2 534.2 45

I 11 7.71 (brs, 1H), 7.43 (s, 1H), 7.24 (d, J = 8.6 Hz, 1H), 6.72 (m,3H), 4.13 (m, 2H), 3.3 (m, 4H), 3.21 (m, 4H), 3.09 (brs, 4H), 2.53 (m,4H), 2.26 (s, 3H), 1.90 (m, 2H), 1.71 (m, 2H), 1.38 (m, 1H), 1.06 (t, J= 8.6 Hz, 3H), 0.77 (m, 2H), 0.39 (m, 2H). 494.5 46

J & K 49 10.1 (brs, 1H), 9.28 (brs, 2H), 8.36 (brs, 1H), 7.31 (brs, 1H),6.88-6.92 (m, 2H), 4.12 (brs, 2H), 2.96- 3.46 (m, 12H), 2.52-2.61 (m,2H), 2.50-2.52 (m, 2H), 1.88 (s, 2H), 1.69 (brs, 2H), 1.11 (t, J = 7.5Hz, 3H). 508.2 47

J 52 8.25 (s, 1H), 8.05 (s, 1H), 7.33 (d, J = 8.7 Hz, 1H), 6.73 (dd, J =2.6 and 8.7 Hz, 1H), 6.68 (brs, 1H), 6.49 (d, J = 2.4 Hz, 1H), 4.00 (s,2H), 3.79 (t, J = 5.0 Hz, 2H), 3.25 (m, 6H), 3.08 (m, 4H), 2.46 (m, 4H),2.23 (s, 3H), 1.94 (m, 1H), 1.71 (m, 2H), 0.84 (m, 2H), 0.58 (m, 2H).534.3 47

J 55 10.5 (brs, 1H), 8.65 (s, 1H), 8.11 (s, 1H), 7.40 (d, J = 8.7 Hz,1H), 7.00 (brs, 1H), 6.81 (dd, J = 2.6 and 8.6 Hz, 1H), 6.56 (d, J = 2.6Hz, 1H), 4.00 (s, 2H), 3.80 (m, 2H), 3.74 (brs, 2H), 3.46 (brs, 6H),3.33 (m, 2H), 3.28 (m, 4H), 2.82 (s, 3H), 1.96 (m, 1H), 1.72 (m, 2H),0.87 (m, 2H), 0.63 (m, 2H). 534.3 48

J 24 8.66 (brs, 1H), 8.01 (brs, 1H), 7.06 (brs, 2H), 6.40- 6.43 (m, 2H),3.51-3.56 (m, 2H), 3.25-3.48 (m, 7H), 3.0- 3.2 (brm, 4H), 2.32-2.38 (m,1H), 2.17-2.24 (m, 3H), 1.57-1.66 (m, 6H), 1.06 (t, J = 7.5 Hz, 3H).516.2 49

J 33 8.62 (s, 1H), 8.04 (s, 1H), 7.27 (d, J = 7.3 Hz, 1H), 7.01 (brs,1H), 6.73 (dd, J = 2.2, 8.6 Hz, 1H), 6.43 (d, J = 2.0 Hz, 1H), 3.69 (s,2H), 3.41 (brs, 4H), 3.20 (m, 4H), 3.07 (brs, 2H), 2.88 (s, 3H), 2.19(brs, 2H), 1.94 (m, 1H), 1.61 (brs, 6H), 0.82 (m, 2H), 0.61 (m, 2H).546.5 50

J 36 8.62 (s, 1H), 8.02 (s, 1H), 7.13 (m, 1H), 6.90 (m, 1H), 6.76 (m,1H), 6.72 (m, 1H), 4.08 (s, 2H), 3.74 (m, 6H), 3.35 (brm, 2H), 3.20(brm, 4H), 3.06 (m, 4H), 2.50 (m, 2H), 1.76 (brm, 2H), 1.57 (brm, 2H, ),1.06 (t, J = 7.5 Hz, 3H). 523.4 51

J 48 8.59 (s, 1H), 8.04 (s, 1H), 7.27 (m, 1H), 6.94 (brm, 1H), 6.74 (m,1H), 6.44 (m, 1H), 4.08 (s, 2H), 3.74 (m, 6H), 3.36 (brm, 2H), 3.23(brm, 4H), 3.05 (m, 4H), 1.96(m, 1H), 1.76 (brm, 2H), 1.60 (brm, 2H, ),0.82 (m, 2H), 0.60 (m, 2H). 535.4 52

J 37 8.57 (s, 1H), 8.18 (s, 1H, FA), 8.04 (s, 1H), 7.24 (m, 1H), 6.93(m, 1H), 6.73 (m, 1H), 6.43 (m, 1H), 4.08 (s, 2H), 3.2-3.7 (m, 6H), 3.20(brm, 2H), 3.06 (m, 4H), 2.44 (m, 4H), 2.20 (s, 3H), 1.95 (m, 1H), 1.75(brm, 2H), 1.60 (brm, 2H), 0.82 (m, 2H), 0.59 (m, 2H). 594.4 52

J 36 11.1 (brs, 1H), 10.23 (brs, 1H), 8.46 (brs, 1H), 7.36 (brs, 1H),6.87 (d, J = 8.8 Hz, 1H), 6.56 (s, 1H), 4.08 (s, 2H), 3.83 (d, J = 8.8Hz, 2H), 3.70-3.76 (m, 2H), 3.09-3.45 (brm, 12H), 2.78 (d, J = 4.4 Hz,3H), 1.93 (brs, 1H), 1.75 (s, 2H), 1.63 (brs, 2H), 0.90 (m, 2H), 0.69(m, 2H). 594.4 53

J 7 10.6 (brs, 1H), 9.69 (brs, 1H), 8.10 (brs, 3H), 6.93 (s, 1H), 4.39(d, J = 13.7 Hz, 2H), 4.09 (s, 2H), 3.75 (d, J = 5.0 Hz, 2H), 3.49 (d, J= 11.3 Hz, 2H), 3.40 (brs, 2H), 3.24 (m, 6H), 3.07 (m, 2H), 2.80 (s,3H), 2.54 (m, 2H), 1.77 (brs, 2H), 1.59 (brs, 2H), 1.12 (t, J = 7.5 Hz,3H).  537.55 54

J 53 8.60 (s, 1H), 8.17 (s, 1H, FA), 8.01 (m, 1H), 7.10 (m, 1H), 6.90(m, 1H), 6.74 (m, 1H), 6.73 (m, 1H), 4.08 (s, 2H), 3.74 (m, 2H), 3.40(brm, 2H), 3.20 (brm, 4H), 3.06 (m, 4H), 2.4-2.6 (m, 6H), 2.21 (s, 3H),1.75 (brm, 2H), 1.57 (brm, 2H, ), 1.07 (t, J = 7.5 Hz, 3H). 536.4 55

I 32 10.6 (brs, 1H), 8.19 (brs, 1H), 7.82 (s, 1H), 7.42 (d, J = 8.6 Hz,1H), 7.13 (brs, 1H), 6.77 (dd, J = 2.3 and 8.7 Hz, 1H), 6.51 (d, J = 2.1Hz, 1H), 4.09 (s, 2H), 3.74 (t, J = 5.2 Hz, 2H), 3.41 (m, 2H), 3.32 (m,3H), 3.28 (m, 5H), 3.01 (brs, 4H), 2.79 (s, 3H), 1.96 (m, 1H), 1.77 (m,2H), 1.66 (m, 2H), 0.84 (m, 2H), 0.60 (m, 2H). 514.4 56

I 14 8.65 (s, 1H), 8.02 (s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.88 (brs,1H), 6.77 (m, 2H), 4.12 (m, 2H), 3.72 (s, 2H), 3.42 (m, 4H), 3.30 (m,2H), 3.14 (brs, 4H), 2.89 (s, 3H), 2.50 (m, 2H), 1.89 (d, J = 7.2 Hz,2H), 1.63 (brs, 2H), 1.07 (t, J = 7.2 Hz, 3H).  536.43 57

I 36 8.07 (s, 1H), 7.74 (s, 1H), 7.16 (d, J = 8.6 Hz, 1H), 6.94 (t, J =5.9 Hz, 1H), 6.76 (s, 1H), 6.71-6.73 (m, 1H), 4.08 (s, 2H), 3.71-3.74(m, 6 H), 3.37-3.39 (m, 2H), 3.21-3.26 (m, 4H), 3.03- 3.07 (m, 4H),2.51-2.55 (m, 2H), 1.74-1.77 (m, 2H), 1.59-1.65 (m, 2H), 1.06 (t, J =7.5 Hz, 3H). 489.4 58

I 25 8.14 (s, 1H, FA), 8.05 (s, 1H), 7.74 (s, 1H), 7.14 (d, J = 8.6 Hz,1H), 6.93 (t, J = 5.9 Hz, 1H), 6.75 (d, J = 2.7 Hz, 1H), 6.71 (dd, J =8.7 and 2.7 Hz, 1H), 4.08 (s, 2H), 3.73 (t, J = 5.5 Hz, 2H), 3.37-3.39(m, 2H), 3.21-3.25 (m, 4H), 3.08 (t, J = 4.8 Hz, 4H), 2.51-2.52 (m, 2H),2.47 (s, 4H), 2.23 (s, 3H), 1.76 (t, J = 5.6 Hz, 2H), 1.63 (m, 2H), 1.05(t, J = 7.5 Hz, 3H). 502.4 59

I 40 8.02 (s, 1H), 7.78 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.00 (t, J =5.8 Hz, 1H), 6.72 (dd, J = 8.8, 2.7 Hz, 1H), 6.46 (d, J = 2.7 Hz, 1H),4.08 (s, 2H), 3.70-3.74 (m, 6H), 3.39-3.41 (m, 2H), 3.26 (q, J = 7.0 Hz,4H), 3.02 (t, J = 4.6 Hz, 4H), 1.93 (m, 1H), 1.76 (t, J = 5.6 Hz, 2H),1.65 (p, J = 6.9 Hz, 2H), 0.82 (m, 2H), 0.56 (m, 2H). 502.4 60

J 29 8.61 (s, 1H), 8.00 (s, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.88 (m, 1H),6.80 (d, J = 2.4 Hz, 1H), 6.71 (dd, J = 2.4 and 8.7 Hz, 1H), 4.08 (s,2H), 3.73 (m, 2H), 3.34 (m, 2H), 3.19 (brs, 4H), 3.10 (brs, 6H), 2.92(m, 1H), 2.35 (m, 2H), 1.90 (s, 2H), 1.76 (m, 2H), 1.56 (m, 2H), 1.10(d, J = 6.9 Hz, 6H), 1.03 (t, J = 7.1 Hz, 3H). 564.6 61

I 9 ¹H NMR (400 MHz, DMSO-d₆ at HT): 7.74 (brs, 1H), 7.44 (s, 1H), 7.32(d, J = 8.6 Hz, 1H), 6.78 (m, 2H), 6.74 (dd, J = 2.4, 8.6 Hz, 1H), 4.11(s, 2H), 3.75 (t, J = 5.6 Hz, 2H), 3.42 (m, 2H), 3.35 (m, 4H), 3.16 (m,4H), 2.65 (m, 4H), 2.54 (m, 2H), 2.37 (s, 3H), 1.82 (m, 2H), 1.72 (m,2H), 1.45 (m, 1H), 1.11 (t, J = 7.4 Hz, 3H), 0.82 (m, 2H), 0.46 (m, 2H).508.3 62

J & K 72 8.58 (s, 1H), 8.04 (s, 1H), 7.25 (s, 1H), 6.94 (s, 1H), 6.72(d, J = 9.0 Hz, 1H), 6.43 (s, 1H), 4.08 (s, 3H), 3.74 (m, 2H), 3.16 (d,3H), 3.03 (m, 4H), 2.88 (s, 4H), 1.90-1.95 (m, 1H), 1.76 (s, 2H), 1.60(s, 2H), 0.80 (m, 2H), 0.56 (m, 2H). 534.2 63

J, K & L 23 8.20 (s, 1H), 8.01 (s, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.60(m, 1H), 6.52 (m, 2H), 4.09 (s, 2H), 3.74 (t, J = 5.5 Hz, 2H), 3.49 (m,2H), 3.44 (m, 2H), 3.38 (m, 2H), 3.24 (m, 4H), 2.64 (m, 2H), 2.54 (m,2H), 2.28 (s, 3H), 1.90 (m, 4H), 1.80 (m, 2H), 1.64 (q, J = 6.4 Hz, 2H),1.09 (t, J = 7.5 Hz, 3H). 550.4 64

J 33 8.74 (s, 1H), 8.07 (s, 1H), 7.19 (d, J = 14.2 Hz, 1H), 7.01 (s,1H), 6.82 (d, J = 9.8 Hz, 1H), 4.08 (s, 2H), 3.73 (s, 2H), 3.20-3.42 (m,7 H), 3.00 (s, 4H), 2.51-2.5 (m, 4H), 2.26 (brs, 3H), 1.76 (brs, 2H),1.61 (brs, 2H), 1.05 (t, J = 7.8 Hz, 3H). 554.2 65

J 30 8.61 (brs, 1H), 8.15 (s, 1H, FA), 8.03 (brs, 1H), 7.16 (brm, 1H),6.92(brm, 1H), 6.77 (s, 1H), 6.72 (m, 1H), 3.57-3.63 (m, 4H), 3.32- 3.40(m, 3H), 3.17-3.28 (m, 3H), 3.08 (m, 4H), 2.57- 2.65 (m, 2H), 2.42-2.52(m, 4H), 2.23 (s, 3H), 2.13 (s, 3H), 1.55 (brm, 2H). 522.4 66

J 42 8.62 (s, 1H), 8.02 (s, 1H), 7.11 (brs, 1H), 6.92 (m, 1H), 6.77 (m,1H), 6.73 (d, J = 8.6 Hz, 1H), 3.60 (brs, 4H), 3.20 (brs, 4H), 3.09(brs, 5H), 2.60 (brs, 3H), 2.36 (brs, 6H), 2.21 (s, 3H), 1.54 (m, 2H),1.05 (t, J = 7.4 Hz, 3H). 536.2 67

J 10 10.8 (brs, 1H), 9.12 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.30(brs, 1H), 6.86 (s, 1H), 4.36 (m, 2H), 3.63 (m, 4H), 3.50 (m, 4H), 3.40(m, 2H), 3.24 (m, 4H), 3.08 (brs, 2H), 2.82 (s, 3H), 2.60 (m, 4H), 1.62(m, 2H), 1.14 (t, J = 7.5 Hz, 3H). 537.6 68

J 48 8.59 (s, 1 H), 7.99 (s, 1H), 7.07 (brs, 1H), 6.94 (s, 1H), 6.64(brs, 2H), 2.62-3.28 (m, 12H), 1.95-2.38 (s, 8H), 1.50-1.80 (m, 9H),1.04 (t, J = 7.5 Hz, 3H). 546.4 69

J 41 11.0 (brs, 1H), 10.10 (brs, 1H), 8.36 (brs, 1H), 7.30 (brd, J =16.6 Hz, 1H), 6.83 (t, J = 10.0 Hz, 2H), 3.92- 4.19 (m, 4H), 3.70 (brd,2H), 3.05-3.54 (brm, 7 H), 2.72 (d, J = 4.8 Hz, 3H), 2.56 (brs, 2H),2.16-2.21 (m, 3H), 1.64-1.93 (brm, 6H), 1.10 (t, J = 7.5 Hz, 3H). 548.370

J 18 11.2 (brs, 1H), 10.3 (brs, 1H), 8.52 (brs, 1H), 7.31 (brm, 1H),6.88 (d, J = 8.8 Hz, 1H), 6.56 (s, 1H), 3.78- 3.87 (m, 2H), 3.0-3.7 (m,16H), 2.78 (s, 3H), 2.55- 2.64 (m, 2H), 1.88-1.97 (m, 1H), 1.5-1.7 (m,2H), 0.90 (m, 2H), 0.70 (m, 2H). 548.4 71

J 56 8.59 (s, 1H), 8.04 (s, 1H), 7.26 (d, J = 8.6 Hz, 1H), 6.92-6.93 (m,1H), 6.72 (dd, J = 8.8, 2.6 Hz, 1H), 6.44 (s, 1H), 3.71 (t, J = 4.5 Hz,4H), 3.56-3.64 (m, 4H), 3.32-3.39 (m, 2H), 3.17- 3.29 (m, 4H), 3.04 (t,J = 4.5 Hz, 4H), 2.58-2.62 (m, 2H), 1.90-1.96 (m, 1H), 1.51-1.62 (m,2H), 0.81 (m, 2H), 0.58 (m, 2H). 535.4 72

J 34 8.62 (s, 1H), 8.02 (s, 1H), 7.13 (d, J = 8.5 Hz, 1H), 6.90 (t, J =5.7 Hz, 1H), 6.78 (d, J = 2.7 Hz, 1H), 6.73 (m, 1H), 3.72 (t, J = 4.6Hz, 4H), 3.55-3.64 (m, 4H), 3.32-3.39 (m, 2H), 3.12-3.28 (m, 4H), 3.06(t, J = 4.6 Hz, 4H), 2.56-2.64 (m, 2H), 2.52 (q, J = 7.5 Hz, 2H), 1.54(brm, 2H), 1.06 (t, J = 7.5 Hz, 3H). 523.4 73

J 16 8.62 (s, 1H), 8.00 (s, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.88 (m, 1H),6.81 (d, J = 1.8 Hz, 1H), 6.72 (d, J = 8.6 Hz, 1H), 3.60 (brs, 4H), 3.31(s, 2H), 3.19 (brs, 5H), 3.10 (s, 6H), 2.60 (brs, 2H), 2.36 (d, J = 6.8Hz, 4H), 1.52 (brs, 2H), 1.09 (d, J = 6.8 Hz, 6H), 1.03 (t, J = 7.5 Hz,3H). 564.1 74

J 51 8.62 (s, 1H), 8.02 (s, 1H), 7.11 (brs, 1H), 6.92 (s, 1H), 6.67 (m,2H), 3.42-3.70 (m, 7H), 2.61-3.39 (brm, 12H), 1.5-2.4 (m, 10H), 1.07 (t,J = 7.5 Hz, 3H). 562.4 75

J & K 81 10.2 (brs, 1H), 9.26 (brs, 1H), 8.42 (brs, 1H), 7.33 (brs, 1H),6.94 (s, 1H), 6.89 (brd, J = 8.7 Hz, 1H), 3.1- 3.7 (brm, 18H), 2.57-2.65(brm, 2H), 2.21 (s, 3H), 1.50-1.65 (m, 2H). 508.2 76

I 5 8.10 (s, 1H), 7.81 (s, 1H), 7.13 (d, J = 8.6 Hz, 1H), 6.69-6.80 (m,3H), 3.60 (t, J = 6.8 Hz, 4H), 3.37 (s, 3H), 3.12-3.25 (m, 8 H), 2.52-2.61 (m, 6H), 2.27 (s, 3H), 1.57 (t, J = 7.1 Hz, 2H), 1.05 (t, J = 7.5Hz, 3H). 546.4 77

I 8 8.09 (s, 1H), 7.80 (s, 1H), 7.04 (d, J = 8.6 Hz, 1H), 6.76 (m, 2H),6.70 (dd, J = 2.5, 8.7 Hz, 1H), 4.08 (s, 2H), 3.74 (m, 2H), 3.36 (m,2H), 3.22 (m, 4H), 3.09 (m, 4H), 2.53 (m, 1H), 2.44 (m, 4H), 2.21 (s,3H), 1.76 (m, 2H), 1.59 (m, 2H), 1.09 (d, J = 6.8 Hz, 6H). 560.5 562.578

J 20 9.58 (brs, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.17 (d, J = 8.5 Hz,1H), 6.54 (s, 1H), 6.50 (d, J = 8.5 Hz, 1H), 4.61 (s, 1H), 4.53 (s, 1H),3.77 (d, J = 7.1 Hz, 1H), 3.69 (d, J = 7.2 Hz, 1H), 3.62 (m, 4H), 3.48(d, J = 9.2 Hz, 1H), 3.37 (m, 4H), 3.25 (m, 2H), 3.01 (d, J = 9.2 Hz,1H), 2.61 (m, 2H), 2.18 (s, 3H), 1.92 (m, 1H), 1.85 (m, 1H), 1.65 (m,2H). 521.4 79

J, K & L 14 8.25 (s, 1H), 8.01 (s, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.57(m, 3H), 3.62 (m, 6H), 3.47 (t, J = 6.0 Hz, 2H), 3.38 (m, 2H), 3.26 (m,4H), 3.13 (brs, 4H), 2.65 (s, 3H), 2.61 (m, 2H), 2.53 (m, 2H), 2.10 (m,2H), 1.61 (q, J = 6.7 Hz, 2H), 1.10 (t, J = 7.4 Hz, 3H). 550.5 80

I 52 8.14 (s, 1H, FA), 8.05 (s, 1H), 7.73 (s, 1H), 7.13 (d, J = 8.6 Hz,1H), 6.93 (t, J = 5.9 Hz, 1H), 6.75 (d, J = 2.8 Hz, 1H), 6.71 (dd, J =8.7 and 2.8 Hz, 1H), 3.58-3.63 (m, 4H), 3.36-3.39 (m, 2H), 3.21-3.27 (m,4H), 3.09 (m, 4H), 2.59 (m, 2H), 2.51- 2.54 (m, 6H), 2.24 (s, 3H),1.55-1.62 (m, 2H), 1.05 (t, J = 5.3 Hz, 3H). 502.4 81

I 34 8.14 (s, 1H, FA), 8.02 (s, 1H), 7.85 (s, 1H), 7.34 (d, J = 8.7 Hz,1H), 6.83 (t, J = 5.9 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 6.44 (s, 1H),3.60 (brs, 4H), 3.38 (brs, 2H), 3.26 (t, J = 7.4 Hz, 4H), 3.04-3.04 (m,4H), 2.59- 2.62 (m, 2H), 2.43 (brs, 4H), 2.21 (s, 3H), 1.89-1.93 (m,1H), 1.56-1.64 (m, 2H), 0.81 (m, 2H), 0.56 (m 2H). 556.2 82

I 44 8.15 (s, 1H, FA), 8.00 (s, 1H), 7.78 (s, 1H), 7.35 (d, J = 8.7 Hz,1H), 6.99 (t, J = 5.9 Hz, 1H), 6.70 (dd, J = 8.8, 2.7 Hz, 1H), 6.44 (d,J = 2.7 Hz, 1H), 3.61 (m, 4H), 3.38 (m, 2H), 3.28 (bm, 4H), 3.04 (4H,m), 2.59- 2.61 (m, 2H), 2.45 (t, J = 4.8 Hz, 4H), 2.22 (s, 3H), 1.92 (m,1H), 1.59-1.65 (m, 2H), 0.81 (m, 2H), 0.55 (m, 2H). 514.2 83

I 32 9.65 (s, 1H), 8.36 (s, 1H), 7.34 (brs, 1H), 7.22 (d, J = 8.3 Hz,1H), 6.95 (s, 1H), 6.90 (m, 1H), 3.87 (m, 4H), 3.61 (brs, 4H), 3.53 (m,2H), 3.41 (brs, 2H), 3.36 (brs, 2H), 3.29 (brs, 2H), 3.14 (m, 2H), 2.94(m, 2H), 2.88 (s, 3H), 2.61 (m, 2H), 1.65 (m, 2H), 1.49 (m, 1H), 1.10(t, J = 7.4 Hz, 3H), 0.89 (m, 2H), 0.54 (m, 2H). 508.3 84

J & K 95 8.59 (s, 1H), 8.01 (s, 1H), 7.10 (s, 1H), 6.90 (t, J = 5.7 Hz,1H), 6.75 (s, 1H), 6.71 (d, J = 8.9 Hz, 1H), 3.57- 3.64 (m, 4H),3.32-3.41 (m, 2H), 3.10-3.27 (m, 4H), 2.99 (t, J = 4.8 Hz, 4H), 2.81 (t,J = 4.7 Hz, 4H), 2.56-2.63 (m, 2H), 2.50- 2.54 (m, 2H), 1.54 (brs, 2H),1.05 (t, J = 7.5 Hz, 3H) [Note: spectrum as free base, one NH missing]522.2 85

J & K 86 10.2 (brs, 1H), 9.29 (brs, 1H), 8.50 (brs, 1H), 7.35 (brs, 1H),6.86 (d, J = 8.7 Hz, 1H), 6.56 (s, 1H), 3.55- 3.64 (m, 6H), 3.35-3.43(m, 6H), 3.15-3.23 (m, 6H), 2.54-2.64 (m, 2H), 1.88- 1.96 (m, 1H),1.52-1.65 (m, 2H), 0.85-0.93 (m, 2H), 0.68 (m, 2H). 534.2 86

J 10 8.77 (s, 1H), 8.09 (s, 1H), 7.22 (d, J = 14.1 Hz, 1H), 7.04 (t, J =5.8 Hz, 1H), 6.86 (d, J = 9.8 Hz, 1H), 3.63 (d, J = 8.9 Hz, 5H),3.36-3.43 (m, 2H), 3.23- 3.32 (m, 4H), 2.92-3.05 (brm, 4H), 2.61-2.65(m, 4H), 2.54-2.59 (m, 2H), 2.37 (brs, 4H), 1.60 (t, J = 7.3 Hz, 2H),1.25 (s, 1H), 1.08 (t, J = 7.5 Hz, 3H). 554.3 87

I 26 8.10 (s, 1H), 7.79 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.78 (m, 2H),6.69 (dd, J = 2.5, 8.6 Hz, 1H), 3.61 (brs, 4H), 3.36 (brs, 2H), 3.21 (m,4H), 3.09 (m, 5H), 2.60 (m, 2H), 2.44 (m, 4H), 2.21 (s, 3H), 1.56 (m,2H), 1.09 (d, J = 6.8 Hz, 6H). 560.5 562.5 88

I 10 8.08 (s, 1H), 7.72 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.92 (brs,1H), 6.78 (d, J = 2.3 Hz, 1H), 6.69 (dd, J = 2.4 and 8.8 Hz, 1H), 3.61(brs, 4H), 3.36 (brs, 2H), 3.23 (brs, 4H), 3.08 (brs, 5H), 2.60 (m, 2H),2.44 (brs, 4H), 2.21 (s, 3H), 1.57 (m, 2H), 1.09 (d, J = 6.8 Hz, 6H).516.4 89

I & K 10 9.12 (brs, 2H), 8.67 (brs, 1H), 7.94 (s, 1H), 7.28 (brs, 1H),6.85(d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 3.70 (m, 2H), 3.66 (m, 2H), 3.57-3.63 (m, 4H), 3.49 (m, 2H), 3.46 (m, 2H), 3.25-3.36 (m, 2H), 3.16-3.23(m, 4H), 2.57-2.63 (m, 2H), 1.88 (m, 1H), 1.65 (m, 2H), 0.88 (m, 2H),0.67 (m, 2H). 500.2 90

J 12 8.44 (s, 1H), 8.02 (d, J = 7.4 Hz, 2H), 6.74 (m, 1H), 6.67 (s, 1H),3.70 (m, 4H), 3.41 (m, 4H), 3.25 (m, 4H), 3.16 (m, 2H), 2.21 (m, 2H),2.14 (s, 3H), 1.65 (m 6H).  494.34 91

J 21 8.70 (s, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.02 (s, 1H), 6.70 (s,1H), 3.42 (brs, 4H), 3.15 (brs, 5H), 2.38 (brs, 4H), 2.20 (s, 5H), 2.11(s, 3H), 1.62 (m, 7H). 507.4 92

M 25 8.07 (s, 1H), 7.86 (s, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.80 (s, 1H),6.75 (m, 1H), 5.94 (brs, 1H), 5.57 (s, 1H), 3.61 (m, 4H), 3.39 (m, 2H),3.27 (m, 2H), 3.10 (m, 4H), 2.98 (m, 2H), 2.60 (m, 2H), 2.54 (m, 2H),2.44 (brs, 4H), 2.21 (s, 3H), 1.57 (m, 2H), 1.06 (t, J = 7.4 Hz, 3H).535.5 93

J 31 8.05 (s, 1H), 7.09 (brs, 1H), 6.42-6.45 (m, 2H), 3.15- 3.57 (m,13H), 2.42-2.46 (m, 2H), 2.32-2.37 (m, 1H), 2.18-2.25 (m, 3H), 1.64- 1.67 (s, 6H), 1.07 (t, J = 7.5 Hz, 3H). 516.2 94

M 21 8.12 (s, 1H), 7.88 (s, 1H), 7.10 (d, J = 8.6 Hz, 1H), 6.71 (dd, J =2.4 and 8.6 Hz, 1H), 6.38 (d, J = 2.2 Hz, 1H), 5.97 (brs, 1H), 5.63 (s,1H), 3.24 (m, 2H), 3.15 (brs, 2H), 3.07 (brs, 4H), 2.97 (m, 2H), 2.44(brs, 4H), 2.21 (s, 3H), 2.19 (m, 2H), 1.91 (m, 1H), 1.63 (m, 6H), 0.82(m, 2H), 0.60 (m, 2H). 531.3 95

M 18 8.14 (s, 1H), 7.95 (s, 1H), 7.86 (s, 1H), 6.72 (s, 1H), 6.03 (brs,1H), 5.65 (s, 1H), 3.42 (brs, 4H), 3.27 (m, 2H), 3.18 (m, 2H), 3.01 (m,2H), 2.38 (m, 4H), 2.20 (brs, 5H), 2.09 (s, 3H), 1.68 (m, 6H). 506.5 96

M 11 8.18 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 6.73 (s, 1H), 6.05 (brs,1H), 5.68 (s, 1H), 3.69 (m, 4H), 3.38 (m, 4H), 3.27 (m, 2H), 3.19 (m,2H), 3.02 (m, 2H), 2.20 (m, 2H), 2.11 (s, 3H), 1.67 (m, 6H). 493.4 98

I 17 7.98 (s, 1 H), 7.81 (s, 1H), 7.29 (d, J = 8.7 Hz, 1H), 6.78 (t, J =5.9 Hz, 1H), 6.66 (dd, J = 8.8 and 2.8 Hz, 1H), 6.39 (d, J = 2.8 Hz,1H), 4.04 (s, 2H), 3.68 (t, J = 5.5 Hz, 2H), 3.34 (m, 2H), 3.21(m, 4H),3.00 (t, J = 4.8 Hz, 4H), 2.38 (t, J = 4.8 Hz, 4H), 2.15 (s, 3H),1.84-1.9 (m, 1H), 1.70-1.73 (m, 2H), 1.59 (m, 2H), 0.75-0.79 (m, 2H),0.49-0.52 (m, 2H). 546.2 548.2 99

J & K 41 9.24 (brs, 2H), 6.85 (dd, J = 8.8 and 2.7 Hz, 1H), 6.55 (d, J =2.7 Hz, 1H), 4.12 (brs, 2H), 3.33-3.40 (brs, 6H), 3.06-3.26 (m, 9 H),1.89 (brs, 3H), 1.68 (brs, 2H), 0.89 (d, J = 8.0 Hz, 2H), 0.67 (m, 2H).520.2 100

I 34 8.07 (s, 1H), 7.80 (s, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.68-6.77 (m,3H), 4.07 (s, 2H), 3.72 (t, J = 5.5 Hz, 2H), 3.37(m, 2H), 3.24(m, 4H),3.07 (t, J = 4.8 Hz, 4H), 2.52 (m, 2H), 2.43 (t, J = 4.8 Hz, 4H), 2.20(s, 3H), 1.75 (t, J = 5.6 Hz, 2H), 1.60 (m, 2H), 1.03 (t, J = 6.4 Hz,3H). 546.2 548.2 101

J 26 8.15 (s, 1H), 7.88 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.71 (d, J =7.4 Hz, 1H), 6.38 (s, 1H), 5.95 (brs, 1H), 5.62 (s, 1H), 3.60 (brs, 4H),3.39 (m, 2H), 3.27 (m, 2H), 3.03 (m, 6H), 2.60 (m, 2H), 2.43 (m, 4H),2.21 (s, 3H), 1.91 (m, 1H), 1.58 (m, 2H), 0.82 (m, 2H), 0.62 (m, 2H).547.6 102

M 23 8.77 (s, 1H), 7.97 (s, 1H), 7.39 (d, J = 8.8 Hz, 2H), 6.86 (d, J =8.9 Hz, 2H), 5.95 (m, 2H), 4.15 (m, 2H), 3.25 (m, 4H), 3.13 (m, 2H),3.06 (m, 4H), 2.54 (m, 4H), 2.27 (s, 3H), 1.92 (m, 2H), 1.76 (m, 2H).493.4 103

M 12 8.74 (s, 1H), 7.96 (s, 1H), 7.37 (d, J = 8.9 Hz, 2H), 6.86 (d, J =8.9 Hz, 2H), 6.06 (m, 1H), 5.93 (s, 1H), 3.30 (m, 2H), 3.22 (m, 2H),3.05 (m, 6H), 2.44 (m, 4H), 2.22 (m, 5H), 1.70 (m, 6H). 491.4 104

M 5 7.67 (s, 1H), 7.64 (s, 1H), 7.16 (d, J = 8.6 Hz, 1H), 6.69 (dd, J =2.4, 8.6 Hz, 1H), 6.38 (d, J = 2.3 Hz, 1H), 5.93 (m, 1H), 5.72 (s, 1H),3.61 (brs, 4H), 3.41 (brs, 2H), 3.31 (m, 2H), 3.05 (brs, 4H), 2.98 (m,2H), 2.60 (m, 2H), 2.43 (brs, 4H), 2.20 (s, 3H), 1.92 (m, 1H), 1.62 (m,2H), 0.82 (m, 2H), 0.59 (m, 2H). 513.5 105

J 45 8.59 (s, 1H), 8.01 (s, 1H), 7.10 (s, 1H), 6.89 (t, J = 5.7 Hz, 1H),6.78 (d, J = 2.8 Hz, 1H), 6.73 (dd, J = 8.7 and 2.8 Hz, 1H), 3.73 (d, J= 11.0 Hz, 1H), 3.53-3.62 (m, 5 H), 3.34-3.45 (brm, 2H), 3.03-3.29 (brm,6H), 2.66- 2.71 (m, 1H), 2.57-2.62 (m, 2H), 2.51-2.53 (m, 2H), 2.35 (t,J = 10.6 Hz, 1H), 2.21 (td, J = 11.1 and 3.2 Hz, 1H), 2.00-2.07 (m, 2H),1.78-1.83 (m, 1H), 1.60- 1.73 (m, 2H), 1.54 (brs, 2H), 1.30-1.40 (m,1H), 1.05 (t, J = 7.5 Hz, 3H). 562.4 106

J 41 8.60 (s, 1H), 8.01 (s, 1H), 7.10 (d, 1H), 6.86 (t, 1H), 6.78 (d, J= 2.8 Hz, 1H), 6.74 (dd, J = 8.7 and 2.8 Hz, 1H), 4.12 (t, J = 5.2 Hz,2H), 3.73 (d, J = 11.0 Hz, 1H), 3.58 (d, J = 11.6 Hz, 1H), 2.99-3.27 (m,8H), 2.68 (dt, J = 11.6 and 3.2 Hz, 1H), 2.51-2.53 (m, 2H), 2.33-2.37(m, 1H), 2.20 (td, J = 11.1 and 3.2 Hz, 1H), 1.99-2.07 (m, 2H), 1.75-1.88 (m, 3H), 1.61-1.73 (m, 4H), 1.30-1.40 (m, 1H), 1.05 (t, J = 7.5 Hz,3H). 548.4 107

J 40 8.58 (s, 1H), 8.04 (s, 1H), 7.25 (s, 1H), 6.94 (s, 1H), 6.74 (d, J= 8.7 Hz, 1H), 6.45 (s, 1H), 3.57-3.68 (m, 5 H), 3.35 (brs, 2H), 3.19-3.26 (m, 4H), 3.08 (brs, 1H), 2.59 (m, 2H), 1.91- 1.94 (m, 1H),1.57-1.90 (m, 2H), 0.81 (m, 2H), 0.59 (m, 2H). 574.3 108

J 27 8.77 (s, 1H), 8.08 (s, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 7.41 (d, J= 7.6 Hz, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.05 (m, 1H), 3.85 (s, 3H),3.23 (m, 4H), 3.12 (brs, 2H), 2.22 (s, 3H), 2.18 (m, 2H), 1.64 (m, 6H).488.3 109

J 35 8.76 (s, 1H), 8.08 (s, 1H), 7.58 (d, J = 6.7 Hz, 2H), 7.51 (d, J =7.0 Hz, 2H), 7.40 (d, J = 8.3 Hz, 1H), 6.99 (t, J = 5.7 Hz, 1H), 3.66(s, 3H), 3.54-3.63 (m, 5H), 3.46-3.47 (m, 1H), 3.19-3.28 (m, 4H), 2.57-2.63 (m, 2H), 2.22 (s, 3H), 1.60 (m, 2H). 504.4 110

M 24 8.76 (brs, 1H), 7.97 (brs, 1H), 7.39 (d, J = 8.8 Hz, 2H), 6.87 (d,J = 8.8 Hz, 2H), 6.00 (brs, 1H), 5.93 (s, 1H), 3.62 (brs, 4H), 3.46(brs, 2H), 3.35 (m, 2H), 3.09 ( t, J = 6.8 Hz, 6H), 2.63 (m, 2H), 2.55(brs, 4H), 2.29 (brs, 3H), 1.67 (t, J = 6.4 Hz, 2H). 507.3 111

J 28 8.62 (s, 1H), 8.02 (s, 1H), 7.05 (d, J = 8.08 Hz, 1H), 6.86 (brs,1H), 6.81 (d, J = 2.4 Hz, 1H), 6.73 (d, J = 2.4, 1H), 4.12 (t, J = 4.7Hz, 2H), 3.10 (brs, 15H), 2.25 (s, 3H), 1.88 (brs, 4H), 1.61 (brs, 2H),1.54 (m, 6H). 562.3 112

J 16 8.59 (brs, 1H), 8.01 (brs, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.89 (m,1H), 6.79 (brs, 1H), 6.73 (dd, J = 8.8 Hz & 2.32 Hz, 1H), 3.60 (m, 4H),3.16 (m, 4H), 3.08 (m, 4H), 3.01 (M, 3 h), 2.59 (t, J = 6.8 Hz, 2H),2.44 (m, 4H), 2.21 (s, 3H), 1.88 (t, J = 8.8 Hz, 2H), 1.73 (m, 2H), 1.52(m, 6H). 576.3 113

J 21 8.61 (s, 1H), 8.01 (s, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.95 (t, J =5.4 Hz, 1H), 6.79 (s, 1H), 6.73 (d, J = 8.6 Hz, 1H), 3.00 (brs, 13H),2.24 (s, 3H), 2.18 (brs, 2H), 1.88 (brs, 2H), 1.69 (m, 6H), 1.51 (m,8H). 560.4 114

J 16 8.65 (brs, 1H), 8.02 (brs, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.88 (m,1H), 6.76 (dd, J = 8.8 and 2.4 Hz, 2H), 4.12 (t, J = 5.2 Hz, 2H), 3.72(s, 2H), 3.42 (dd, J = 9.6 Hz & 4.4 Hz, 4H), 3.25 (m, 5H), 3.14 (brs,2H), 2.89 (s, 2H), 2.55 (d, J = 7.6 Hz, 2H), 1.88 (t, J = 5.2 Hz, 2H),1.63 (brs, 2H), 1.08 (m, 3H). 536.2 115

J 9 8.65 (brs, 1H), 8.03 (brs, 1H), 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.92(m, 1H), 6.81 (s, 1H), 6.76 (dd, J = 11.2 and 2.4 Hz, 1H), 3.73 (s, 2H),3.60 (m, 4H), 3.43 (m, 4H), 3.32 (m, 2H), 3.22 (brs, 4H), 2.90 (s, 3H),2.59 (brs, 2H), 2.53 (brs, 2H), 1.56 (brs, 2H), 1.08 (t, J = 7.5 Hz,3H). 550.3 116

J 54 8.52 (s, 1H), 8.02 (s, 1H), 7.10 (brs, 1H), 6.89 (s, 1H), 6.36 (dd,J = 8.6 and 2.6 Hz, 1H), 6.03 (s, 1H), 4.26 (s, 1H), 3.59 (t, J = 11.8Hz, 4H), 3.34-3.35 (m, 3H), 3.15-3.26 (brs, 4 H), 3.10 (d, J = 9.1 Hz,1H), 2.77 (d, J = 9.4 Hz, 1H), 2.59 (s, 2H), 2.27 (s, 3H), 1.86-1.92 (m,2H), 1.75 (s, 1H), 1.55 (brs, 2H), 0.79 (m, 2H), 0.55 (m, 2H). 560.4 117

J 48 8.54 (s, 1H), 8.02 (s, 1H), 7.12 (brs, 1H), 6.86 (s, 1H), 6.38 (d,J = 8.6 Hz, 1H), 6.04 (s, 1H), 4.29 (s, 1H), 4.12 (t, J = 5.3 Hz, 2H),3.09-3.28 (m, 6H), 2.80 (s, 1H), 2.32 (brs, 3H), 1.90 (m, 4H), 1.78(brs, 1H), 1.64 (brs, 2H), 0.80 (m, 2H), 0.55 (m, 2H). 546.2 118

I 14 8.01 (t, J = 1.0 Hz, 1H), 7.82 (s, 1H), 7.19 (d, J = 8.5 Hz, 1H),6.82 (t, J = 6.0 Hz, 1H), 6.19 (m, 1H), 5.92 (d, J = 2.6 Hz, 1H), 3.84(t, J = 7.0 Hz, 2H), 3.44 (t, J = 6.5 Hz, 2H), 3.22 (t, J = 7.0 Hz, 3H),3.13 (m, 3H), 2.19 (t, J = 6.1 Hz, 2H), 2.07 (s, 6H), 1.90 (m, 1H),1.61-1.68 (m, 6H), 0.80 (m, 2H), 0.53 (m, 2H). 542.2 544.4 119

J 19 8.53 (s, 1H), 8.00 (s, 1H), 7.01 (brs, 1H), 6.87 (s, 1H), 6.37-6.39(m, 2H), 4.27 (s, 1H), 3.60 (brs, 5H), 3.43 (brs, 4H), 3.13-3.24 (brm,4H), 2.78 (brs, 1H), 2.59- 2.62 (m, 3H), 2.15-2.47 (m, 5H), 1.53-1.88(brm, 4H), 1.05 (t, J = 7.5 Hz, 3H). 548.4 120

J 12 8.53 (s, 1H), 8.00 (s, 1H), 7.01 (s, 1H), 6.83-6.87 (m, 1H),6.37-6.39 (m, 2H), 4.26 (s, 1H), 4.09-4.15 (m, 2H), 3.36-3.48 (brm, 2H),3.12-3.27 (m, 6H), 2.78 (s, 1H), 2.45-2.47 (m, 3H), 2.28 (brs, 3H),1.61-1.88 (brm, 7H), 1.05 (t, J = 7.5 Hz, 3H). 534.2 121

J 40 8.60 (s, 1H), 8.01 (s, 1H), 7.10 (s, 1H), 6.86 (s, 1H), 6.78 (d, J= 2.7 Hz, 1H), 6.74 (dd, J = 8.8 and 2.8 Hz, 1H), 4.12 (t, J = 5.2 Hz,2H), 3.73 (d, J = 11.0 Hz, 1H), 3.58 (d, J = 11.6 Hz, 1H), 3.23 (brs, 3H), 2.97- 3.17 (brm, 6H), 2.63-2.71 (m, 1H), 2.50-2.53 (m, 2H), 2.35 (t,J = 10.6 Hz, 1H), 2.21 (t, J = 11.1 Hz, 1H), 2.02-2.08 (m, 2H), 1.85-1.91 (m, 2H), 1.77-1.85 (m, 1H), 1.56-1.75 (m, 4 H), 1.31-1.39 (m, 1H),1.05 (t, J = 7.5 Hz, 3H). 548.2 122

J 29 8.59 (s, 1H), 8.01 (s, 1H), 7.10 (s, 1H), 6.90 (t, J = 5.7 Hz, 1H),6.78 (d, J = 2.8 Hz, 1H), 6.74 (dd, J = 8.7 and 2.8 Hz, 1H), 3.73 (d, J= 11.0 Hz, 1H), 3.54-3.64 (m, 5 H), 3.32-3.37 (m, 2 H), 3.13-3.27 (m, 4H), 2.98- 3.04 (m, 2H), 2.68 (d, J = 11.6 Hz, 1H), 2.56-2.63 (m, 2H),2.49-2.55 (m, 2H), 2.35 (t, J = 10.6 Hz, 1H), 2.21 (t, J = 11.1 Hz, 1H),2.02-2.07 (m, 2H), 1.79- 1.85 (m, 1H), 1.65-1.73 (m, 2H), 1.54 (brs,2H), 1.32- 1.40 (m, 1H), 1.05 (t, J = 7.5 Hz, 3H). 562.2 123

J 17 8.52 (s, 1H), 8.00 (s, 1H), 7.00 (brs, 1H), 6.83 (s, 1H), 6.37 (m,2H), 4.23 (s, 1H), 4.11 (s, 2H), 3.31-3.40 (m, 2H), 2.91-3.29 (m, 8H),2.74 (d, J = 9.3 Hz, 1H), 2.45 (m, 2H), 2.23 (s, 3H), 1.80-1.93 (m, 3H),1.73 (d, J = 9.3 Hz, 1H), 1.43-1.70 (brm, 2H), 1.05 (t, J = 7.5 Hz, 3H).534.2 124

J 23 8.52 (s, 1H), 8.00 (s, 1H), 7.01 (brs, 1H), 6.87 (s, 1H), 6.37-6.39(m, 2H), 4.25 (s, 1H), 3.60 (brs, 4H), 3.33- 3.51 (m, 3H), 2.99-3.27 (m,5H), 2.73-2.80 (m, 1H), 2.51-2.64 (m, 3H), 2.43 (m, 2H), 2.26 (s, 3H),1.81-1.90 (m, 1H), 1.75 (d, J = 9.4 Hz, 1H), 1.52 (brs, 2H), 1.05 (t, J= 7.5 Hz, 3H). 548.2 125

J 57 8.51 (s, 1H), 8.05 (d, J = 16.2 Hz, 1H), 7.10 (brs, 1H), 6.89 (s,1H), 6.36 (dd, J = 8.6 and 2.6 Hz, 1H), 6.02 (d, J = 2.6 Hz, 1H), 4.23(s, 1H), 3.60 (d, J = 12.3 Hz, 4H), 3.35 (brs, 3H), 3.15-3.29 (m, 5H),3.08 (m, 1H), 2.73 (d, J = 9.3 Hz, 1H), 2.58 (m, 2H), 2.44 (d, J = 10.1Hz, 1H), 2.22 (s, 3H), 1.86-1.93 (m, 1H), 1.82 (d, J = 9.2 Hz, 1H), 1.71(d, J = 9.2 Hz, 1H), 1.55 (brs, 2H), 0.79 (m, 2H), 0.54 (m, 2H). 560.4126

J 14 8.55 (s, 1H), 8.02 (s, 1H), 7.12 (s, 1H), 6.95 (t, J = 5.8 Hz, 1H),6.21 (dd, J = 8.5 and 2.5 Hz, 1H), 5.91 (d, J = 2.5 Hz, 1H), 3.85 (t, J= 7.0 Hz, 2H), 3.45 (t, J = 6.5 Hz, 2H), 3.13 (m, 4 H), 2.19 (m, 2H),2.07 (s, 6 H), 1.90 (m, 1H), 1.67 (m, 4 H), 0.80 (t, J = 8.1 Hz, 2H),0.54 (m, 2H). 531.4 127

J 7 8.49 (s, 1H), 8.07 (s, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.02 (t, J =5.4 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 2.5 and 8.80 Hz,1H), 4.39 (s, 2H), 3.62 (m, 4H), 3.37 (s, 2H), 3.32 (m, 3H), 3.27 (s,2H), 3.09 (m, 4H), 2.61 (m, 2H), 2.49 (m, 4H), 2.24 (s, 3H), 1.91 (s,2H), 1.59 (m, 2H). 552.3 128

J 16 8.71 (brs, 1H), 8.10 (brs, 1H), 7.93 (brs, 1H), 6.93 (brs, 1H),6.69 (s, 1H), 4.13 (m, 2H), 3.46 (m, 4H), 3.16 (m, 6H), 2.54 (m, 2H),2.44 (m, 4H), 2.26 (brs, 3H), 1.89 (m, 2H), 1.57 (m, 2H), 1.07 (t, J =7.5 Hz, 3H). 523.3 129

J 45 8.77 (s, 1H), 8.09 (s, 1H), 7.22 (d, J = 14.1 Hz, 1H), 7.04 (t, J =5.8 Hz, 1H), 6.86 (d, J = 9.8 Hz, 1H), 3.63 (d, J = 8.9 Hz, 5H), 3.40(m, 2H), 3.23-3.32 (m, 4H), 2.92-3.05 (brm, 4H), 2.63 (m, 4H), 2.57 (m,2H), 2.37 (brs, 4H), 1.60 (t, J = 7.3 Hz, 2H), 1.25 (s, 1H), 1.08 (t, J= 7.5 Hz, 3H). 493.3 130

J 27 8.52 (s, 1H), 8.03 (s, 1H), 7.13 (brm, 1H), 6.96 (brm, 1H), 6.58(d, J = 8.7 Hz, 1H), 6.27 (s, 1H), 4.16 (s, 2H), 3.05-3.27 (m, 7H), 2.42(m, 2H), 2.21 (m, 4H), 2.04 (s, 3H), 1.82 (m, 4H), 1.59-1.66 (m, 7H),0.79 (m, 2H), 0.55 (m, 2H). 558.4 131

J 30 8.64 (s, 1H), 8.06 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 7.13 (d, J =2.7 Hz, 1H), 7.00 (t, J = 5.8 Hz, 1H), 6.94 (dd, J = 2.8 and 8.9 Hz,1H), 3.60-3.62 (m, 4H), 3.37 (m, 2H) 3.15-3.29 (m, 4H), 3.12 (t, J = 4.8Hz, 4H), 2.60 (m, 2H), 2.42 (t, J = 4.8 Hz, 4H), 2.20 (s, 3H), 1.56 (s,2H). 586.2 588.2 132

J 44 8.68 (s, 1H), 8.06 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.01 (t, J =5.9 Hz, 1H), 6.98 (d, J = 2.8 Hz, 1H), 6.90 (dd, J = 2.8 and 8.9 Hz,1H), 3.61 (m, 4H), 3.38 (s, 2H), 3.14-3.25 (m, 8H), 2.60 (m, 2H), 2.45(brs, 4H), 2.23 (s, 3H), 1.57 (t, J = 7.4 Hz, 2H). 542.2 133

J 29 8.52 (s, 1H), 8.03 (s, 1H), 7.13 (s, 1H), 6.90 (s, 1H), 6.59 (d, J= 8.7 Hz, 1H), 6.27 (s, 1H), 4.17 (s, 2H), 3.60 (s, 4H), 3.36 (s, 2H),3.22 (brm, 4H), 2.59 (s, 2H), 2.42 (d, J = 10.7 Hz, 2H), 2.24 (d, J =10.6 Hz, 2H), 2.04 (s, 3H), 1.79-1.90 (m, 5H), 1.55 (brm, 2H), 0.79 (m,2H), 0.54 (m, 2H). 574.3 134

J 4 9.70 (brs, 1H), 8.09 (s, 1H), 7.98 (brs, 1H), 7.1 (m, 1H), 6.83 (m,2H), 5.8 (s, 1H), 3.63 (m, 4H), 3.41 (m, 2H), 3.36 (m, 4H), 3.06 (m,4H), 2.63 (m, 2H), 2.46 (m, 4H), 2.21 (s, 3H), 1.68 (m, 2H), 1.50 (s,6H). 566.3 135

J 7 9.71 (brs, 1H), 8.09 (s, 1H), 8.00 (d, J = 5.7 Hz, 1H), 7.0 (brs,1H), 6.85 (brs, 1H), 6.83 (s, 1H), 5.8 (s, 1H), 4.13 (t, J = 5.1 Hz,2H), 3.37 (m, 2H), 3.23 (m, 4H), 3.06 (m, 4H), 2.44 (m, 4H), 2.21 (s,3H), 1.89 (m, 2H), 1.76 (m, 2H), 1.50 (s, 6H). 552.3 136

J 25 8.61 (s, 1H), 8.07 (s, 1H), 7.18 (s, 1H), 6.95 (t, J = 5.8 Hz, 1H),6.27 (dd, J = 2.6 and 8.5 Hz, 1H), 5.97 (d, J = 2.6 Hz, 1H), 3.92 (t, J= 7.0 Hz, 2H), 3.65 (d, J = 10.9 Hz, 4H), 3.54 (t, J = 6.5 Hz, 2H), 3.40(m, 2H), 3.25 (m, 5H), 2.65 (m, 2H), 2.17 (s, 6H), 1.94 (m, 1H), 1.60(brs, 2H), 0.85 (m, 2H), 0.57 (m, 2H). 548.4 137

J 18 8.61 (s, 1H), 8.07 (s, 1H), 7.18 (s, 1H), 6.95 (s, 1H), 6.27 (m,1H), 5.95 (d, J = 2.6 Hz, 1H), 3.95 (t, J = 7.4 Hz, 2H), 3.66 (d, J =9.4 Hz, 4H), 3.49 (t, J = 6.6 Hz, 2H), 3.35-3.45 (m, 7H), 2.98 (m, 2H),2.90 (brm, 2H), 2.65 (m, 2H), 2.44 (s, 6H), 1.95 (m, 1H), 1.61 (brs,2H), 0.85 (m, 2H), 0.58 (m, 2H). 562.4 138

J 30 8.54 (s, 1H), 8.01 (s, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.88 (t, J =5.8 Hz, 1H), 6.64 (d, J = 2.6 Hz, 1H), 6.59-6.63 (m, 1H), 4.18 (s, 2H),4.07 (s, 2H), 3.73 (t, J = 5.4 Hz, 2H), 3.19 (brs, 4H), 2.40-2.47 (m,4H), 2.29 (m, 2H), 2.04 (s, 3H), 1.74-1.87 (m, 6H), 1.55 (brs, 2H), 1.04(t, J = 7.5 Hz, 3H). 562.4 139

J 50 8.53 (s, 1H), 8.02 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.87 (brm,1H), 6.64 (s, 1H), 6.60 (d, J = 8.7 Hz, 1H), 4.18 (s, 2H), 3.21 (m, 4H),2.92 (brs, 2H), 2.44 (m, 4H), 2.28 (m, 2H), 2.05 (m, 3H), 1.84 (m, 4H),1.59 (brs, 2H), 1.13 (s, 6H), 1.04 (t, J = 7.5 Hz, 3H). 546.4 140

J 53 8.53 (s, 1H), 8.01 (s, 1H), 7.02 (s, 1H), 6.87 (s, 1H), 6.64 (s,1H), 6.60 (d, J = 8.8 Hz, 1H), 4.18 (s, 2H), 3.15 (m, 6H), 2.43 (m, 4H),2.28 (m, 2H), 2.05 (s, 3H), 1.83 (m, 6H), 1.62 (brs, 2H), 1.25 (s, 6H),1.04 (t, J = 7.5 Hz, 3H). 576.4 141

J 11 8.61 (brs, 1H), 8.02 (s, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.8 (t, J =5.8 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 6.73 (dd, J = 2.7 and 8.7 Hz,1H), 3.21 (brs, 4H), 3.10 (m, 4H), 2.91 (m, 4H), 2.44 (m, 4H), 2.21 (s,3H), 1.60 (brs, 2H), 1.14 (s, 6H), 1.05 (t, J = 7.5 Hz, 3H). 520.3 142

J 24 8.62 (s, 1H), 8.02 (s, 1H), 7.11 (d, J = 8.6 Hz, 1H), 6.8 (t, J =5.9 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 6.73 (dd, J = 2.5 and 8.6 Hz,1H), 3.61 (brs, 2H), 3.35 (s, 2H), 3.19 (m, 4H), 3.10 (m, 6H), 2.54 (q,2H), 2.45 (m, 4H), 2.21 (s, 3H), 1.54 (brs, 2H), 1.06 (s, 6H), 1.06 (t,J = 6.8 Hz, 3H). 564.3 143

J 24 8.73 (s, 1H), 8.04 (s, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.09 (m, 2H),6.96 (m, 1H), 3.60 (m, 4H), 3.36 (brm, 2H), 3.1-3.2 (brm, 4H), 2.97 (t,J = 8.9 Hz, 1H), 2.73 (brm, 2H), 2.52-2.62 (m, 4H), 2.40 (m, 4H), 2.24(m, 1H), 1.76 (m, 2H), 1.55 (s, 2H), 1.08 (t, J = 7.5 Hz, 3H). 521.2 144

J 18 8.53 (brs, 1H), 7.99 (brs, 1H), 7.02 (brs, 1H), 6.86 (brm, 1H),6.35 (m, 2H), 3.58 (m, 4H), 3.41 (m, 4H), 3.32 (m, 4H), 3.21 (m, 2H),3.02 (t, J = 8.5 Hz, 2H), 2.78 (m, 1H), 2.57 (m, 2H), 2.21 (s, 6H), 2.14(m, 2H), 1.80 (m, 2H), 1.05 (t, J = 7.5 Hz, 3H). 550.4 145

J 26 8.53 (brs, 1H), 7.99 (brs, 1H), 7.02 (brs, 1H), 6.86 (brm, 1H),6.35 (m, 2H), 3.58 (m, 4H), 3.41 (m, 4H), 3.32 (m, 4H), 3.21 (m, 2H),3.02 (t, J = 8.5 Hz, 2H), 2.78 (m, 1H), 2.57 (m, 2H), 2.21 (s, 6H), 2.14(m, 2H), 1.80 (m, 2H), 1.05 (t, J = 7.5 Hz, 3H). 550.4 146

J 21 8.72 (s, 1H), 8.04 (s, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.07 (s, 1H),7.02 (m, 1H), 6.96 (t, J = 5.9 Hz, 1H), 3.62 (m, 4H), 3.1-3.6 (brm, 8H),3.00 (m, 2H), 2.53- 2.61 (m, 4H), 2.32 (m, 3H), 2.21 (t, J = 12.2 Hz,2H), 1.78 (m, 2H), 1.68 (m, 2H), 1.56 (m, 2H), 1.08 (t, J = 7.6 Hz, 3H).535.2 147

J 15 8.5 (s, 1H), 8.06 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 6.9 (m, 1H),6.90 (s, 1H), 6.87 (dd, J = 1.6 and 8.8 Hz Hz, 1H), 5.25 (brs, 2H), 4.39(s, 2H), 4.12 (t, J = 4.8 Hz, 2H), 3.27 (s, 3H), 3.17 (m, 4H), 3.09 (m,4H), 2.44 (m, 4H), 2.21 (s, 3H), 1.89 (m, 2H), 1.70 (m, 2H). 538.3 148

J 19 8.6 (s, 1H), 8.04 (s, 1H), 7.23 (d, J = 8.3 Hz, 1H), 6.9 (t, J =6.8 Hz, 1H), 6.72 (dd, J = 2.4 and 8.6 Hz, 1H), 6.42 (d, J = 2.4 Hz,1H), 3.26 (brs, 2H), 3.14 (m, 4H), 3.06 (m, 4H), 2.43 (m, 4H), 2.21 (s,3H), 1.93 (m, 1H), 1.81 (t, J = 6.2 Hz, 2H), 1.65 (m, 2H), 1.25 (s, 6H),0.81 (m, 2H), 0.58 (m, 2H). 562.3 149

J 30 8.57 (s, 1H), 8.01 (s, 1H), 7.07 (brm, 1H), 6.89 (t, J = 5.8 Hz,1H), 6.70 (s, 1H), 6.66 (d, J = 8.8 Hz, 1H), 4.24 (brm, 2H), 3.48-3.58(brm, 6H), 3.21 (brm, 4H), 3.03-3.24 (brm, 6H), 2.54- 2.63 (m, 2H), 1.89(brm, 2H), 1.62 (m, 2H), 1.51 (brm, 2H), 1.38 (s, 9H), 1.05 (t, J = 7.5Hz, 3H). 648.4 150

K 42 10.13 (br s, 1H), 9.75 (brs, 1H), 9.22 (br s, 1H), 8.48 (brs, 1H),7.32 (brs, 1H), 6.83 (m, 2H), 4.44 (s, 2H), 3.19-3.70 (brm, 8H), 2.93-3.11 (m, 4H), 2.59 (brs, 4H), 2.15 (m, 2H), 2.08 (m, 4H), 1.56-1.75(brm, 2H), 1.13 (t, J = 7.5 Hz, 3H). 548.3 151

J 20 8.60 (s, 1H), 8.06 (s, 1H), 7.17 (brm, 1H), 7.00 (t, J = 6.0 Hz,1H), 6.23 (m, 1H), 5.95 (d, J = 2.5 Hz, 1H), 3.94 (m, 2H), 3.47 (m 2H),3.0-3.32 (m, 7H), 2.79 (brs, 2H), 2.37 (s, 6H), 2.25 (m, 2H), 1.94 (m,1H), 1.72 (s, 4H), 1.64 (brs, 2H), 0.84 (m, 2H), 0.58 (m, 2H). 546.4 152

J 40 8.57 (s, 1H), 7.98 (m, 1H), 7.04 (d, J = 8.0 Hz, 1H), 6.88 (t, J =8.0 Hz, 1H), 6.24 (m, 2H), 3.96 (q, J = 7.5 Hz, 2H), 3.61 (m, 4H), 3.53(m, 2H), 3.36 (m, 2H), 3.20 (m, 4H), 3.10 (m, 2H), 2.61 (s, 7H), 2.49(m, 4H), 1.54 (brs, 2H), 1.04 (m, 3H). 550.2 153

J 34 9.36 (s, 1H), 8.11 (s, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7.06 (brs,1H), 6.87 (d, J = 8.8 Hz, 2H), 3.61 (m, 4H), 3.33-3.42 (m, 6 H), 3.04(t, J = 4.8 Hz, 4H), 2.61-2.63 (m, 2H), 2.43 (t, J = 4.8 Hz, 4H), 2.20(s, 3H), 1.69 (m, 2H). 508.4

Example 130. Biochemical Assay for ULK1.2 (SEQ. ID NO: 1)

Activity of ULK1 kinase was determined spectroscopically using a coupledpyruvate kinase/lactate dehydrogenase assay that continuously monitorsthe ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al.Science (2000) 289: 1938-1942). Assays were conducted in 384-well plates(100 uL final volume) using 19 nM ULK1 (Eurofins CAT #14-959), 0.25mg/mL myelin basic protein, 1.5 units pyruvate kinase, 2.1 units lactatedehydrogenase, 1 mM phosphoenol pyruvate, 0.28 mM NADH and 1 mM ATP inassay buffer (100 mM Tris, pH 7.5, 15 mM MgCl₂, 0.5 mM DTT, 0.1%octyl-glucoside, 0.002% (w/v) BSA, and 0.002% Triton X-100). Inhibitionof ULK1 was measured by adding serial diluted test compound (final assayconcentration of 1% DMSO). A decrease in absorption at 340 nm wasmonitored continuously for 6 hours at 30° C. on a multi-mode microplatereader (BioTek). The reaction rate was calculated using the 2-3 h timeframe. The reaction rate at each concentration of compound was convertedto percent inhibition using controls (i.e. reaction with no testcompound and reaction with a known inhibitor) and IC₅₀ values werecalculated by fitting a four-parameter sigmoidal curve to the data usingPrism (GraphPad software).

ULK1 protein sequence (residues 1-314 withN-terminal His tag; SEQ. ID NO: 1)MSYYHHHHHHDYDIPTTENLYFQGAMDPFFMEPGRGGTETVGKFEFSRKDLIGHGAFAVVFKGRHREKHDLEVAVKCINKKNLAKSQTLLGKEIKILKELKHENIVALYDFQEMANSVYLVMEYCNGGDLADYLHAMRTLSEDTIRLFLQQIAGAMRLLHSKGIIHRDLKPQNILLSNPAGRRANPNSIRVKIADFGFARYLQSNMMAATLCGSPMYMAPEVIMSQHYDGKADLWSIGTIVYQCLTGKAPFQASSPQDLRLFYEKNKTLVPTIPRETSAPLRQLLLALLQRNHKDRMDFDEFFHHPFLDASPSVRKSPPVPVPSYPSSGSGSSS SSSSTSHLAS

Example 131. Biochemical Assay for ULK1.3 (SEQ. ID NO: 2)

Activity of ULK1 kinase was determined spectroscopically using a coupledpyruvate kinase/lactate dehydrogenase assay that continuously monitorsthe ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al.Science (2000) 289: 1938-1942). Assays were conducted in 384-well plates(100 uL final volume) using 0.1 nM ULK1 (from Beryllium), 0.075 mMpeptide substrate (YANWLAASIYLDGKKK (SEQ ID NO: 5)), 1.5 units pyruvatekinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenol pyruvate, 0.28mM NADH and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl₂,0.5 mM DTT, 0.004% (w/v) BSA, and 0.004% Triton X-100). Inhibition ofULK1 was measured by adding serial diluted test compound (final assayconcentration of 1% DMSO). A decrease in absorption at 340 nm wasmonitored continuously for 6 hours at 30° C. on a multi-mode microplatereader (BioTek). The reaction rate was calculated using the 2-3 h timeframe. The reaction rate at each concentration of compound was convertedto percent inhibition using controls (i.e. reaction with no testcompound and reaction with a known inhibitor) and IC₅₀ values werecalculated using software routines in Prism (GraphPad software).

ULK1 protein sequence (residues 1-283; SEQ. ID NO: 2)MEPGRGGTETVGKFEFSRKDLIGHGAFAVVFKGRHRAAHDLEVAVKCINKKNLAKSQTLLGKEIKILKELKHENIVALYDFQEMANSVYLVMEYCNGGDLADYLHAMRTLSEDTIRLFLQQIAGAMRLLHSKGIIHRDLKPQNILLSNPAGRRANPNSIRVKIADFGFARYLQSNMMAATLCGSPMYMAPEVIMSQHYDGKADLWSIGTIVYQCLTGKAPFQASSPQDLRLFYEKNKTLVPTIPRETSAPLRQLLLALLQRNHKDRMDFDEFF HHPFLDASPS

Example 132. Biochemical Assay for ULK2 (SEQ. ID NO: 3)

Activity of ULK2 kinase was determined spectroscopically using a coupledpyruvate kinase/lactate dehydrogenase assay that continuously monitorsthe ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al.Science (2000) 289: 1938-1942). Assays were conducted in 384-well plates(100 uL final volume) using 9.7 nM ULK2 (Eurofins CAT #14-772), 0.25mg/mL myelin basic protein, 1.5 units pyruvate kinase, 2.1 units lactatedehydrogenase, 1 mM phosphoenol pyruvate, 0.28 mM NADH and 1 mM ATP inassay buffer (100 mM Tris, pH 7.5, 15 mM MgCl₂, 0.5 mM DTT, 0.1%octyl-glucoside, 0.002% (w/v) BSA, and 0.002% Triton X-100). Inhibitionof ULK2 was measured by adding serial diluted test compound (final assayconcentration of 1% DMSO). A decrease in absorption at 340 nm wasmonitored continuously for 6 hours at 30° C. on a multi-mode microplatereader (BioTek). The reaction rate was calculated using the 2-3 h timeframe. The reaction rate at each concentration of compound was convertedto percent inhibition using controls (i.e. reaction with no testcompound and reaction with a known inhibitor) and IC₅₀ values werecalculated by fitting a four-parameter sigmoidal curve to the data usingPrism (GraphPad software).

ULK2 protein sequence (residues 1-306 withN-terminal GST and His tag; SEQ. ID NO: 3)MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLEVLFQGPEFMEVVGDFEYSKRDLVGHGAFAVVFRGRHRQKTDWEVAIKSINKKNLSKSQILLGKEIKILKELQHENIVALYDVQELPNSVFLVMEYCNGGDLADYLQAKGTLSEDTIRVFLHQIAAAMRILHSKGIIHRDLKPQNILLSYANRRKSSVSGIRIKIADFGFARYLHSNMMAATLCGSPMYMAPEVIMSQHYDAKADLWSIGTVIYQCLVGKPPFQANSPQDLRMFYEKNRSLMPSIPRETSPYLANLLLGLLQRNQKDRMDFEAFFSHPFLEQGPVKKSCPVPVPMYSGSVSGSSCGSSPSCRFASHHHHHH

TABLE 1 Inhibition of biochemical activity of ULK1 and ULK2 kinases byexemplary compounds shown in Table I. Example (Compound) Number ULK1.2ULK1.3 ULK2.2 1 + + + + 2 + + + 3 + + + 4 + + + + + 5 + + + + 6 + + + +7 + + + + + 8 + + + + + 9 + + 10 + + 11 + + 12 + + 13 + + 14 + + +15 + + 16 + 17 + 18 + + + + + 19 + + + 20 + + + 21 + + 22 + + + +23 + + + + + 24 + 26 + 27 + + 28 + 29 + + + 30 + + 31 + 32 + + 33 + 34 +35 + + 36 + + 37 + 38 + 39 + + + + 40 + 41 + + + 42 + 43 + + 44 +45 + + + 46 + + + 47 + + 48 + + + 49 + + + 50 + + + + + + +51 + + + + + + + 52 + + + + 53 + + 54 + + + 55 + + + + + + 56 + +57 + + + + + + + + 58 + + + + + + + 59 + + + + + + + + 60 + 61 + + + +62 + 63 + + 64 + + + 65 + + + 66 + + + + 67 + 68 + 69 + 70 + + + +71 + + + + + 72 + + + + + + 73 + + + + 74 + + 75 + 76 + + 77 + +78 + + + 79 + 80 + + 81 + 82 + + 83 + + + + 84 + + + 85 + 86 + + 87 + +88 + + 89 + + + 90 + + + + + + + + 91 + + + + + + + 92 + 93 + + + 94 + +95 + + + + + + + 96 + + + + + + + + 97 + + + 98 + + 99 + + + 100 + +101 + 102 + 103 + 104 + + + 105 + 106 + 107 + 108 + + + + + + + +109 + + + + + + + + 110 + 111 + 112 + 113 + 114 + + 115 + + + 116 + +117 + + 118 + + 119 + 120 + 121 + 122 + 123 + 124 + 125 + 126 + 127 +128 + 129 + + 130 + + 131 + 132 + 133 + + + 134 + + + + 135 + + + 136 +137 + 138 + + + 139 + + + + 140 + + + 141 + + 142 + 143 + 144 + 145 +146 + + 147 + 148 + 150 + 151 + 152 + For Table 1, “+” refers to an IC₅₀greater than 1 nM and less than or equal to 25 nM; “+ +” refers to anIC₅₀ greater than 25 nM and less than or equal to 100 nM; “+ + +” refersto an IC₅₀ greater than 100 nM and less than or equal to 500 nM; and“+ + + +” refers to an IC₅₀ greater than 500 nM.

Example 133. Cellular Inhibition of ULK Kinase Substrate ATG13 ProteinpATG13 Levels of Mutant KRas A549 Cells after Treatment with ULKInhibitors in Combination with Trametinib

A549 (KRAS mutant) human lung cancer cells (6,000 cells/well) were addedto a 384-well tissue-culture treated plate in 50 μL of pre-warmed DMEMmedium supplemented with 10% characterized fetal bovine serum(Invitrogen, Carlsbad, Calif.), 100 units/mL penicillin G, and 100 μg/mLstreptomycin and allowed to grow overnight at 37° C., 5% CO2, and 95%humidity. The following day, 10 μL of media containing trametinib orDMSO as a control was added to wells. The final concentration oftrametinib in wells was 250 nM. A dose response of a test compound (0.6μL per well) was added. DMSO (0.6 μL) was added to control wells. Theplate was briefly shaken to mix wells and then incubated at 37° C.overnight. The next day, the media was aspirated and cells were washedwith Dulbecco's Phosphate Buffered Saline (Gibco). Cells were lysedusing MPER lysis buffer (Pierce, Rockford, Ill.) containing HaltPhosphatase and Protease Inhibitors (Pierce, Rockford, Ill.) andPhosphatase inhibitor cocktail 2 (Sigma, St. Louis, Mo.) at 4° C. for 10minutes with shaking.

Cellular levels of phospho-Serine 318 ATG13 (pATG13) were measured viaan ELISA method. Total ATG13 Antibody (Cell Signaling Cat #13273) wasused to coat the wells. The plate was incubated at 4° C. overnight andwashed with ELISA wash buffer (Biolegend Cat #421601). The wells werethen blocked with assay diluent (Biolegend Cat #421203) for 1 hour atroom temperature. Plate wells were washed with ELISA wash buffer. Celllysate was added to wells and incubated at room temperature for 2 hours.Plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13antibody (Rockland Immunochemicals Cat #600-401-C49) was diluted inassay diluent and added to each well and incubated at room temperaturefor 1 hour. Plate wells were washed with ELISA wash buffer. Streptavidinlinked to horseradish peroxidase (Thermo Fisher Cat #21140) was dilutedin assay diluent and added to each well and incubated at roomtemperature for 1 hour. Plate wells were washed with ELISA wash buffer.High sensitivity TMB substrate (Biolegend Cat #421101) was added to eachwell and incubated at room temperature for 20 minutes. The reaction wasstopped with 2N Sulfuric Acid. The plate was analyzed at on a platereader measuring absorbance at 450 nm and 540 nm (background). Signalwas calculated by first subtracting the background absorbance at 540 nmfrom the absorbance at 450 nm for each well. Next, the backgroundcorrected absorbance at 450 nm from blank wells was subtracted from testwells. Data was compared to control wells to determine % ATG13phosphorylation. GraphPad Prism was used to calculate IC₅₀ values.

Example 134. pATG13 Levels of Mutant KRas MiaPaCa-2 Cells afterTreatment with ULK Inhibitors in Combination with Trametinib

MiaPaCa-2 human pancreatic cancer cells (10000 cells/well) were added toa 384-well tissue-culture treated plate in 50 μL of pre-warmed DMEMmedium supplemented with 10% characterized fetal bovine serum(Invitrogen, Carlsbad, Calif.), 100 units/mL penicillin G, 100 pg/mLstreptomycin, and 2.5% Horse Serum and allowed to grow overnight at 37°C., 5% CO2, and 95% humidity. The following day, 10 μL of mediacontaining trametinib or DMSO as a control was added to wells. The finalconcentration of trametinib in wells was 250 nM. A dose response of atest compound (0.6 μL per well) was added. DMSO (0.6 μL) was added tocontrol wells. The plate was briefly shaken to mix wells and thenincubated at 37° C. overnight. The next day, the media was aspirated andcells were washed with Dulbecco's Phosphate Buffered Saline (Gibco).Cells were lysed using MPER lysis buffer (Pierce, Rockford, Ill.)containing Halt Phosphatase and Protease Inhibitors (Pierce, Rockford,Ill.) and Phosphatase inhibitor cocktail 2 (Sigma, St. Louis, Mo.) at 4°C. for 10 minutes with shaking.

Cellular levels of phospho-Serine 318 ATG13 (pATG13) were measured viaan ELISA method. Total ATG13 Antibody (Cell Signaling Cat #13273) wasused to coat the wells. The plate was incubated at 4° C. overnight andwashed with ELISA wash buffer (Biolegend Cat #421601). The wells werethen blocked with assay diluent (Biolegend Cat #421203) for 1 hour atroom temperature. Plate wells were washed with ELISA wash buffer. Celllysate was added to wells and incubated at room temperature for 2 hours.Plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13antibody (Rockland Immunochemicals Cat #600-401-C49) was diluted inassay diluent and added to each well and incubated at room temperaturefor 1 hour. Plate wells were washed with ELISA wash buffer. Streptavidinlinked to horseradish peroxidase (Thermo Fisher Cat #21140) was dilutedin assay diluent and added to each well and incubated at roomtemperature for 1 hour. Plate wells were washed with ELISA wash buffer.High sensitivity TMB substrate (Biolegend Cat #421101) was added to eachwell and incubated at room temperature for 20 minutes. The reaction wasstopped with 2N Sulfuric Acid. The plate was analyzed at on a platereader measuring absorbance at 450 nm and 540 nm (background). Signalwas calculated by first subtracting the background absorbance at 540 nmfrom the absorbance at 450 nm for each well. Next, the backgroundcorrected absorbance at 450 nm from blank wells was subtracted from testwells. Data was compared to control wells to determine % ATG13phosphorylation. GraphPad Prism was used to calculate IC₅₀ values.

Example 135. pATG13 Levels of Mutant KRas HCT-116 Cells after Treatmentwith ULK Inhibitors in Combination with Trametinib

HCT-116 human colon cancer cells (10000 cells/well) were added to a384-well tissue-culture treated plate in 50 μL of pre-warmed DMEM mediumsupplemented with 10% characterized fetal bovine serum (Invitrogen,Carlsbad, Calif.), 100 units/mL penicillin G, and 100 pg/mL streptomycinand allowed to grow overnight at 37° C., 5% CO2, and 95% humidity. Thefollowing day, 10 μL of media containing trametinib or DMSO as a controlwas added to wells. The final concentration of trametinib in wells was250 nM. A dose response of a test compound (0.6 μL per well) was added.DMSO (0.6 μL) was added to control wells. The plate was briefly shakento mix wells and then incubated at 37° C. overnight. The next day, themedia was aspirated and cells were washed with Dulbecco's PhosphateBuffered Saline (Gibco). Cells were lysed using MPER lysis buffer(Pierce, Rockford, Ill.) containing Halt Phosphatase and ProteaseInhibitors (Pierce, Rockford, Ill.) and Phosphatase inhibitor cocktail 2(Sigma, St. Louis, Mo.) at 4° C. for 10 minutes with shaking.

Cellular levels of phospho-Serine 318 ATG13 (pATG13) were measured viaan ELISA method. Total ATG13 Antibody (Cell Signaling Cat #13273) wasused to coat the wells. The plate was incubated at 4° C. overnight andwashed with ELISA wash buffer (Biolegend Cat #421601). The wells werethen blocked with assay diluent (Biolegend Cat #421203) for 1 hour atroom temperature. Plate wells were washed with ELISA wash buffer. Celllysate was added to wells and incubated at room temperature for 2 hours.Plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13antibody (Rockland Immunochemicals Cat #600-401-C49) was diluted inassay diluent and added to each well and incubated at room temperaturefor 1 hour. Plate wells were washed with ELISA wash buffer. Streptavidinlinked to horseradish peroxidase (Thermo Fisher Cat #21140) was dilutedin assay diluent and added to each well and incubated at roomtemperature for 1 hour. Plate wells were washed with ELISA wash buffer.High sensitivity TMB substrate (Biolegend Cat #421101) was added to eachwell and incubated at room temperature for 20 minutes. The reaction wasstopped with 2N Sulfuric Acid. The plate was analyzed at on a platereader measuring absorbance at 450 nm and 540 nm (background). Signalwas calculated by first subtracting the background absorbance at 540 nmfrom the absorbance at 450 nm for each well. Next, the backgroundcorrected absorbance at 450 nm from blank wells was subtracted from testwells. Data was compared to control wells to determine % ATG13phosphorylation. GraphPad Prism was used to calculate IC₅₀ values.

Example 136. pATG13 Levels of Mutant BRAF A375 Cells after Treatmentwith ULK Inhibitors in Combination with Trametinib

A375 human malignant melanoma cancer cells (20000 cells/well) were addedto a 96-well tissue-culture treated plate in 100 μL of pre-warmed DMEMmedium supplemented with 10% characterized fetal bovine serum(Invitrogen, Carlsbad, Calif.), 100 units/mL penicillin G, and 100 μg/mLstreptomycin and allowed to grow overnight at 37° C., 5% CO₂, and 95%humidity. The following day, 100 μL of media containing trametinib orDMSO as a control was added to wells. The final concentration oftrametinib in wells was 250 nM. A dose response of a test compound (0.5μL per well) was added. DMSO (0.5 μL) was added to control wells. Theplate was briefly shaken to mix wells and then incubated at 37° C.overnight. The next day, the media was aspirated and cells were washedwith Dulbecco's Phosphate Buffered Saline (Gibco). Cells were lysedusing MPER lysis buffer (Pierce, Rockford, Ill.) containing HaltPhosphatase and Protease Inhibitors (Pierce, Rockford, Ill.) andPhosphatase inhibitor cocktail 2 (Sigma, St. Louis, Mo.) at 4° C. for 10minutes with shaking.

Cellular levels of phospho-Serine 318 ATG13 (pATG13) were measured viaan ELISA method. Total ATG13 Antibody (Cell Signaling Cat #13273) wasused to coat the wells. The plate was incubated at 4° C. overnight andwashed with ELISA wash buffer (Biolegend Cat #421601). The wells werethen blocked with assay diluent (Biolegend Cat #421203) for 1 hour atroom temperature. Plate wells were washed with ELISA wash buffer. Celllysate was added to wells and incubated at room temperature for 2 hours.Plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13antibody (Rockland Immunochemicals Cat #600-401-C49) was diluted inassay diluent and added to each well and incubated at room temperaturefor 1 hour. Plate wells were washed with ELISA wash buffer. Streptavidinlinked to horseradish peroxidase (Thermo Fisher Cat #21140) was dilutedin assay diluent and added to each well and incubated at roomtemperature for 1 hour. Plate wells were washed with ELISA wash buffer.High sensitivity TMB substrate (Biolegend Cat #421101) was added to eachwell and incubated at room temperature for 20 minutes. The reaction wasstopped with 2N Sulfuric Acid. The plate was analyzed at on a platereader measuring absorbance at 450 nm and 540 nm (background). Signalwas calculated by first subtracting the background absorbance at 540 nmfrom the absorbance at 450 nm for each well. Next, the backgroundcorrected absorbance at 450 nm from blank wells was subtracted from testwells. Data was compared to control wells to determine % ATG13phosphorylation. GraphPad Prism was used to calculate IC₅₀ values.

Example 137. pATG13 Levels of Mutant HRas T24 Cells after Treatment withULK Inhibitors in Combination with Trametinib

T24 human urinary bladder cancer cells (25000 cells/well) were added toa 96-well tissue-culture treated plate in 100 μL of pre-warmed DMEMmedium supplemented with 10% characterized fetal bovine serum(Invitrogen, Carlsbad, Calif.), 100 units/mL penicillin G, and 100 μg/mLstreptomycin and allowed to grow overnight at 37° C., 5% CO2, and 95%humidity. The following day, 100 μL of media containing trametinib orDMSO as a control was added to wells. The final concentration oftrametinib in wells was 250 nM. A dose response of a test compound (0.5μL per well) was added. DMSO (0.5 μL) was added to control wells. Theplate was briefly shaken to mix wells and then incubated at 37° C.overnight. The next day, the media was aspirated and cells were washedwith Dulbecco's Phosphate Buffered Saline (Gibco). Cells were lysedusing MPER lysis buffer (Pierce, Rockford, Ill.) containing HaltPhosphatase and Protease Inhibitors (Pierce, Rockford, Ill.) andPhosphatase inhibitor cocktail 2 (Sigma, St. Louis, Mo.) at 4° C. for 10minutes with shaking.

Cellular levels of phospho-Serine 318 ATG13 (pATG13) were measured viaan ELISA method. Total ATG13 Antibody (Cell Signaling Cat #13273) wasused to coat the wells. The plate was incubated at 4° C. overnight andwashed with ELISA wash buffer (Biolegend Cat #421601). The wells werethen blocked with assay diluent (Biolegend Cat #421203) for 1 hour atroom temperature. Plate wells were washed with ELISA wash buffer. Celllysate was added to wells and incubated at room temperature for 2 hours.Plate wells were washed with ELISA wash buffer. Biotinylated pS318-ATG13antibody (Rockland Immunochemicals Cat #600-401-C49) was diluted inassay diluent and added to each well and incubated at room temperaturefor 1 hour. Plate wells were washed with ELISA wash buffer. Streptavidinlinked to horseradish peroxidase (Thermo Fisher Cat #21140) was dilutedin assay diluent and added to each well and incubated at roomtemperature for 1 hour. Plate wells were washed with ELISA wash buffer.High sensitivity TMB substrate (Biolegend Cat #421101) was added to eachwell and incubated at room temperature for 20 minutes. The reaction wasstopped with 2N Sulfuric Acid. The plate was analyzed at on a platereader measuring absorbance at 450 nm and 540 nm (background). Signalwas calculated by first subtracting the background absorbance at 540 nmfrom the absorbance at 450 nm for each well. Next, the backgroundcorrected absorbance at 450 nm from blank wells was subtracted from testwells. Data was compared to control wells to determine % ATG13phosphorylation. GraphPad Prism was used to calculate IC₅₀ values.

TABLE 2 Inhibition of ULK kinase in mutant Ras or mutant BRAF cell linesby exemplary compounds shown in Table I. Example A549 MiaPaca- HCT-116T24 A375 (Compound) pATG13 2 pATG13 pATG13 pATG13 pATG13 No. ELISA ELISAELISA ELISA ELISA 4 + + + + + + 7 + + + + 8 + + 10 + + + + 11 + + + + +12 + + 13 + + 14 + + + + + 16 + + 19 + + + + 20 + + + + + + +21 + + + + + 23 + + + + 26 + + + 27 + + + + 28 + + + + 30 + + + + +31 + + + + + 33 + + + 34 + + + + + 35 + + + + 36 + + + + + + + +37 + + + + + + 39 + + + + + 40 + + 41 + + + + + 42 + + 44 + +46 + + + + + + + + 47 + + + + + + + + + + 50 + + + + + + + +52 + + + + + 54 + + + 55 + + + + + + 57 + + + + 58 + + + +60 + + + + + + + + 62 + + + 65 + + + 66 + + + + + 67 + + + + 68 + +69 + + + 70 + + + + + 71 + + + + 72 + + + 73 + + + + + + 74 + + + +75 + + + + + + + 76 + + + + 79 + + + 80 + + + + + + 81 + + + 82 + + + +84 + + + + + + + 85 + + + + + + 86 + + + + + + + 87 + + + + + +88 + + + + + 91 + + + + + + 92 + + + + + 99 + + + + + + + 100 + + + +101 + + + + + + + 102 + + + + 103 + + 105 + + + 106 + + + 107 + +109 + + + + 110 + + + 112 + + + + 116 + + + 117 + + + 119 + + +120 + + + + 122 + + + + + 123 + 124 + + 125 + + 126 + + + 127 + + + +129 + + + + + 130 + + + + + + 131 + + + + + 132 + + + 137 + + +147 + + + + 148 + + 150 + + + For Table 2, “+” refers to an IC₅₀ greaterthan 10 nM and less than or equal to 100 nM; “+ +” refers to an IC₅₀greater than 100 nM and less than or equal to 300 nM; “+ + +” refers toan IC₅₀ greater than 300 nM and less than or equal to 600 nM; and “+ + ++” refers to an IC₅₀ greater than 600 nM.

Example 138. Biochemical Assay for LRRK2 (SEQ. ID NO: 4)

Activity of LRRK2 kinase was determined spectroscopically using acoupled pyruvate kinase/lactate dehydrogenase assay that continuouslymonitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindleret al. Science (2000) 289: 1938-1942). Assays were conducted in 384-wellplates (100 μL final volume) using 26.4 nM LRRK2 (Thermo Fisher), 0.1 mMpeptide substrate (RLGRDKYKTLRQIRQ (SEQ ID NO: 6)), 1.5 units pyruvatekinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenol pyruvate, 0.28mM NADH and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl₂,0.5 mM DTT, 0.004% (w/v) BSA, and 0.004% Triton X-100). Inhibition ofLRRK2 was measured by adding serial diluted test compound (final assayconcentration of 1% DMSO). A decrease in absorption at 340 nm wasmonitored continuously for 6 hours at 30° C. on a multi-mode microplatereader (BioTek). The reaction rate was calculated using the 2-3 h timeframe. The reaction rate at each concentration of compound was convertedto percent inhibition using controls (i.e. reaction with no testcompound and reaction with a known inhibitor) and IC₅₀ values werecalculated using software routines in Prism (GraphPad software).

LRRK2 protein sequence (residues 970-2528; SEQ. ID NO: 4)MAPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLVPRHNQTSLYKKAGTMHSDSISSLASEREYITSLDLSANELRDIDALSQKCCISVHLEHLEKLELHQNALTSFPQQLCETLKSLTHLDLHSNKFTSFPSYLLKMSCIANLDVSRNDIGPSVVLDPTVKCPTLKQFNLSYNQLSFVPENLTDVVEKLEQLILEGNKISGICSPLRLKELKILNLSKNHISSLSENFLEACPKVESFSARMNFLAAMPFLPPSMTILKLSQNKFSCIPEAILNLPHLRSLDMSSNDIQYLPGPAHWKSLNLRELLFSHNQISILDLSEKAYLWSRVEKLHLSHNKLKEIPPEIGCLENLTSLDVSYNLELRSFPNEMGKLSKIWDLPLDELHLNFDFKHIGCKAKDIIRFLQQRLKKAVPYNRMKLMIVGNTGSGKTTLLQQLMKTKKSDLGMQSATVGIDVKDWPIQIRDKRKRDLVLNVWDFAGREEFYSTHPHFMTQRALYLAVYDLSKGQAEVDAMKPWLFNIKARASSSPVILVGTHLDVSDEKQRKACMSKITKELLNKRGFPAIRDYHFVNATEESDALAKLRKTIINESLNFKIRDQLVVGQLIPDCYVELEKIILSERKNVPIEFPVIDRKRLLQLVRENQLQLDENELPHAVHFLNESGVLLHFQDPALQLSDLYFVEPKWLCKIMAQILTVKVEGCPKHPKGIISRRDVEKFLSKKRKFPKNYMSQYFKLLEKFQIALPIGEEYLLVPSSLSDHRPVIELPHCENSEIIIRLYEMPYFPMGFWSRLINRLLEISPYMLSGRERALRPNRMYWRQGIYLNWSPEAYCLVGSEVLDNHPESFLKITVPSCRKGCILLGQVVDHIDSLMEEWFPGLLEIDICGEGETLLKKWALYSFNDGEEHQKILLDDLMKKAEEGDLLVNPDQPRLTIPISQIAPDLILADLPRNIMLNNDELEFEQAPEFLLGDGSFGSVYRAAYEGEEVAVKIFNKHTSLRLLRQELVVLCHLHHPSLISLLAAGIRPRMLVMELASKGSLDRLLQQDKASLTRTLQHRIALHVADGLRYLHSAMIIYRDLKPHNVLLFTLYPNAAIIAKIADYGIAQYCCRMGIKTSEGTPGFRAPEVARGNVIYNQQADVYSFGLLLYDILTTGGRIVEGLKFPNEFDELEIQGKLPDPVKEYGCAPWPMVEKLIKQCLKENPQERPTSAQVFDILNSAELVCLTRRILLPKNVIVECMVATHHNSRNASIWLGCGHTDRGQLSFLDLNTEGYTSEEVADSRILCLALVHLPVEKESWIVSGTQSGTLLVINTEDGKKRHTLEKMTDSVTCLYCNSFSKQSKQKNFLLVGTADGKLAIFEDKTVKLKGAAPLKILNIGNVSTPLMCLSESTNSTERNVMWGGCGTKIFSFSNDFTIQKLIETRTSQLFSYAAFSDSNIITVVVDTALYIAKQNSPVVEVWDKKTEKLCGLIDCVHFLREVMVKENKESKHKMSYSGRVKTLCLQKNTALWIGTGGGHILLLDLSTRRLIRVIYNFCNSVRVMMTAQLGSLKNVMLVLGYNRKNTEGTQKQKEIQSCLTVWDINLPHEVQNLEKHIEVRKELAEKMRRTSVE

TABLE 3 Inhibition of LRRK2 kinase activity by exemplary compounds shownin Table I. Example (Compound) No. LRRK2 1 + + + + 2 + 5 + + 14 + 18 +33 + + + 35 + 37 + + 39 + 41 + 46 + + 47 + + 48 + + 49 + + 50 + 51 +52 + 55 + + 56 + + 58 + + 61 + + + + 64 + 66 + + 68 + + 69 + + + 70 +74 + + + 76 + + 78 + + 79 + + 84 + + 86 + 87 + + + 90 + + + 92 + + + +93 + + 99 + 105 + 106 + + 107 + + 108 + 109 + 111 + + 112 + + 113 + +114 + 115 + + 116 + 117 + 118 + 119 + + 120 + + 122 + 123 + + 124 + +125 + 126 + 127 + + + 129 + + + + 131 + + 132 + 147 + + + 148 + + ForTable 3, “+” refers to an IC₅₀ greater than 1 nM and less than or equalto 100 nM; “+ +” refers to an IC₅₀ greater than 100 nM and less than orequal to 300 nM; “+ + +” refers to an IC₅₀ greater than 300 nM and lessthan or equal to 600 nM; and “+ + + +” refers to an IC₅₀ greater than600 nM.

Example 139. Evaluation of ULK Inhibitors in Pancreatic DuctalAdenocarcinoma (PDAC) In Vitro and In Vivo

ULK inhibitors will be evaluated in PDAC flux assays, and the IC₅₀ ofthe compounds in a panel of multiple PDAC cell lines, including cellsderived from primary tumors of a Trp53^(lox/+), LSL-Kras^(G12D),Rosa-rtTA^(LSL), p48Cre⁺) will be determined using a clonogenicity 2Dassay and a 3D organoid assay, in the absence or the presence oftrametinib.

The inhibition of autophagic flux using flux reporters in PDAC tumors invivo using syngeneic orthotopic models after single and multiple doseswill be evaluated.

The therapeutic efficacy of ULK inhibitors in PDAC models will beevaluated by (i) assessing the tumor kinetics of PDAC subcutaneously;(ii) assessing the tumor kinetics of PDAC (KPC implanted C57 black mice)orthotopically in the pancreas in syngeneic models; (iii) assessingtumor growth kinetics in syngeneic models with ULK inhibitors and MEKinhibitors; (iv) assessing the compounds in the PDAC autochthonousmodel; (v) assessing histological changes in the tumor microenvironment;(vi) assessing the changes in the immune cell infiltrates in the tumorsupon inhibition by ULK inhibitors; (vii) assessing the efficacy of ULKinhibitors in combination with immune checkpoint blockade.

EQUIVALENTS

While specific embodiments have been discussed, the above specificationis illustrative and not restrictive. Many variations of the embodimentswill become apparent to those skilled in the art upon review of thisspecification. The full scope of what is disclosed should be determinedby reference to the claims, along with their full scope of equivalents,and the specification, along with such variations.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in this specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained.

What is claimed is:
 1. A compound represented by:

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, ortautomer thereof, wherein: W is CH or N; X is CH or N; Y is C(R³) or N;R¹ is selected from the group consisting of halogen, cyano, C₁-C₅alkyl,and C₃-C₅cycloalkyl, wherein each C₁-C₅alkyl and C₃-C₅cycloalkyl may beoptionally substituted by one, two or three independent occurrences offluorine; R² is selected from the group consisting of H, halogen, cyano,C₁-C₅alkyl, C₃-C₆cycloalkyl, C₂-C₅alkenyl, C₂-C₅alkynyl, C₁-C₅alkoxy,and C₁-C₅alkoxy-C₂-C₅alkyl, wherein each C₁-C₅alkyl, C₃-C₆cycloalkyl,C₂-C₅alkenyl, C₂-C₅alkynyl, and C₁-C₅alkoxy may be optionallysubstituted by one, two, or three independent occurrences of fluorine orcyano; each occurrence of R³ and R³³ is independently selected from thegroup consisting of H, halogen, C₁-C₆alkyl, and C₁-C₆alkoxy, whereineach C₁-C₆alkyl and C₁-C₆alkoxy may be optionally substituted by one ormore independent occurrences of fluorine; R⁴ is selected from the groupconsisting of B, D, NR⁶R⁹, NR—(C(R¹⁰)₂)_(p)—NR⁶R⁶, C(O)—NR⁶R⁹, C(O)—B,C(O)-D, and CN; B is selected from an N-linked heterocyclyl having atleast one nitrogen and optionally having an additional ring nitrogen oroxygen and heteroaryl, wherein B may be optionally substituted on one ormore available carbons by R⁷ and may be optionally substituted on anavailable nitrogen by R⁹; D is selected from a C-linked heterocyclylhaving at least one nitrogen and optionally having an additional ringnitrogen or oxygen and heteroaryl, wherein D may be optionallysubstituted on one or more available carbons by R⁷ and may be optionallysubstituted on an available nitrogen by R⁹; each occurrence of R⁵ isindependently selected from the group consisting of H, C₁-C₆alkyl,C₃-C₆cycloalkyl, and heterocyclyl, wherein each C₁-C₆alkyl andC₃-C₆cycloalkyl may be optionally substituted by one or more independentoccurrences of fluorine; each occurrence of R⁷ is independently selectedfrom the group consisting of H, C₁-C₆alkyl, C₃-C₆cycloalkyl, cyano, and(C(R¹⁰)₂)_(h)—NR⁹R⁹, wherein each C₁-C₆alkyl and C₃-C₆cycloalkyl may beoptionally substituted by one or more independent occurrences offluorine, or two R⁷ are joined together with the atom to which they areattached to form oxo; each occurrence of R⁶ and R⁹ is independentlyselected from the group consisting of H, C₁-C₆alkyl, C₃-C₆cycloalkyl,C₁-C₅alkoxy-C₂-C₅alkyl, C(═O)R⁵, SO₂R⁵, C-linked heterocyclyl having atleast one nitrogen and optionally having an additional ring nitrogen oroxygen, and heteroaryl, wherein each C₁-C₆alkyl and C₃-C₆cycloalkyl maybe optionally substituted by one or more independent occurrences offluorine; each occurrence of R¹⁰ is independently selected from thegroup consisting of H, C₁-C₃alkyl, and C₃-C₅cycloalkyl, wherein eachC₁-C₃alkyl and C₃-C₅cycloalkyl may be optionally substituted by one ormore independent occurrences of fluorine, or two R¹⁰ are joined togetherwith the carbon to which they are attached to form a C₃-C₅cycloalkyl; Zis selected from the group consisting of a 4 membered lactam ring boundthrough the nitrogen atom and a 6-10 membered lactam ring bound throughthe nitrogen atom, wherein a lactam ring atom may optionally be oxygenor NR⁶ when the lactam ring is a 6-10 membered ring and an availablecarbon atom on 4 membered lactam ring or a 6-10 membered lactam isoptionally substituted by R³⁶; each occurrence of R³⁶ is independentlyselected from C₁-C₆alkyl and C₃-C₆cycloalkyl, wherein each C₁-C₆alkyland C₃-C₆cycloalkyl may be optionally substituted by one or moreindependent occurrences of fluorine, or two R³⁶ are joined together withthe carbon to which they are attached to form a C₃-C₆cycloalkyl; h is 1,2, or 3; m is 0, 1, 2, or 3; n is 2, 3, or 4; and p is 2 or 3; providedthat both X and Y are not N.
 2. The compound of claim 1, wherein Z isselected from:

wherein V is selected from the group consisting of oxygen, C(R³⁴)₂, andNR⁶; each occurrence of R³⁴ is independently selected from H and R³⁶,wherein each occurrence of R³⁶ is independently selected from C₁-C₆alkyland C₃-C₆cycloalkyl, or two R³⁶ are joined together with the carbon towhich they are attached to form a C₃-C₆cycloalkyl; q is 0, 1, 2, or 3;and r is 2 or 4; provided that, if q is 0, then r is not
 2. 3. Thecompound of claim 1, wherein Z is selected from:

wherein V is selected from the group consisting of oxygen, C(R³⁴)₂, andNR⁶; each occurrence of R³⁴ is independently selected from H and R³⁶,wherein each occurrence of R³⁶ is independently selected from C₁-C₆alkyland C₃-C₆cycloalkyl, or two R³⁶ are joined together with the carbon towhich they are attached to form a C₃-C₆cycloalkyl; q is 0, 1, 2, or 3;and r is 2 or 3; provided that, if q is 0, then r is not
 2. 4. Thecompound of claim 2, wherein Z is selected from the group consisting of:


5. The compound of claim 1, wherein R⁴ is selected from the groupconsisting of:

wherein u is 1 or
 2. 6. The compound of claim 1, wherein R¹ is selectedfrom the group consisting of halogen, C₁-C₅alkyl, and C₃-C₅cycloalkyl,wherein C₁-C₅alkyl may be optionally substituted with one, two, or threeoccurrences of fluorine.
 7. The compound of claim 1, wherein R² isselected from the group consisting of C₁₋₂alkyl and C₃₋₄cycloalkyl. 8.The compound of claim 1, wherein R² is selected from the groupconsisting of chloro and bromo.
 9. The compound of claim 1, wherein n is3.
 10. The compound of claim 1 represented by:

or a pharmaceutically acceptable salt thereof, wherein: n is 2, 3, or 4;Z is selected from the group consisting of:

R¹ is selected from the group consisting of halogen, cyano, C₁-C₅alkyl,and C₃-C₅cycloalkyl, wherein each C₁-C₅alkyl and C₃-C₅cycloalkyl may beoptionally substituted by one, two or three independent occurrences offluorine; R² is selected from the group consisting of halogen,C₁-C₂alkyl and C₃-C₄cycloalkyl; R⁴ is selected from the group consistingof:

each occurrence of R⁶ and R⁹ is independently selected from the groupconsisting of H, C₁-C₆alkyl, C₃-C₆cycloalkyl, C(═O)R⁵, SO₂R⁵, , whereineach C₁-C₆alkyl and C₃-C₆cycloalkyl may be optionally substituted by oneor more independent occurrences of fluorine; each occurrence of R⁵ isindependently selected from the group consisting of H, C₁-C₆alkyl,C₃-C₆cycloalkyl, and heterocyclyl, wherein each C₁-C₆alkyl andC₃-C₆cycloalkyl may be optionally substituted by one or more independentoccurrences of fluorine; each occurrence of R⁷ is independently selectedfrom the group consisting of H, C₁-C₆ alkyl, and C₃-C₆cycloalkyl,wherein each C₁-C₆alkyl and C₃-C₆cycloalkyl may be optionallysubstituted by one or more independent occurrences of fluorine, or twoR⁷ are joined together with the atom to which they are attached to formoxo; D is selected from a C-linked heterocyclyl having at least onenitrogen and optionally having an additional ring nitrogen or oxygen andheteroaryl, wherein D may be optionally substituted on one or moreavailable carbons by R⁷ and may be optionally substituted on anavailable nitrogen by R⁹; and each occurrence of R³⁴ is independentlyselected from H and R³⁶, wherein each occurrence of R³⁶ is independentlyselected from C₁-C₆alkyl and C₃-C₆cycloalkyl, wherein each C₁-C₆alkyland C₃-C₆cycloalkyl may be optionally substituted by one or moreindependent occurrences of fluorine, or two R³⁶ are joined together withthe carbon to which they are attached to form a C₃-C₆cycloalkyl.
 11. Thecompound of claim 10, wherein R¹ is selected from the group consistingof halogen, C₁-C₅alkyl, and C₃-C₅cycloalkyl, wherein C₁-C₅alkyl may beoptionally substituted with one, two, or three occurrences of fluorine.12. The compound of claim 11, wherein R¹ is CF₃.
 13. The compound ofclaim 1, wherein R² is selected from the group consisting of H,C₃-C₄cycloalkyl, C₁-C₅alkyl, and halogen.
 14. The compound of claim 10,wherein R⁴ is selected from the group consisting of:


15. The compound of claim 10, wherein Z is selected from the groupconsisting of:


16. The compound of claim 1 represented by:

wherein R¹ is selected from the group consisting of CF₃, CF₂H, bromo,chloro, and cyclopropyl; R² is selected from the group consisting ofC₁-C₂alkyl, C₃-C₄cycloalkyl, and halogen; and R⁹ is selected from thegroup consisting of C₁-C₃alkyl, H, and C₃-C₅cycloalkyl.
 17. The compoundof claim 1 represented by:

wherein R¹ is selected from the group consisting of bromo, chloro, CF₃,CF₂H, and cyclopropyl; R² is selected from the group consisting ofC₁-C₂alkyl, C₃-C₄cycloalkyl, and halogen; and R⁹ is selected from thegroup consisting of C₁-C₃alkyl, H, and C₃-C₅cycloalkyl.
 18. The compoundof claim 17, wherein R¹ is CF₃; R² is selected from the group consistingof C₁-C₂alkyl, C₃-C₄cycloalkyl, bromo, and chloro; and R⁹ is selectedfrom C₁-C₃alkyl and H.
 19. The compound of claim 1 selected from thegroup consisting of:1-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-cyclopropyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((5-chloro-2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,(R)-1-(3-ethyl-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyrrolidine-3-carbonitrile,1-(3-((2-((4-(4-cyclopropylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-ethyl-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,4-(3-cyclopropyl-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1-methylpiperazin-2-one,1-(3-((5-bromo-2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-methyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((5-chloro-2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-cyclopropyl-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(4-(2-fluoroethyl)piperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((5-chloro-2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(4-acetylpiperazin-1-yl)-2-cyclopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,(S)-1-(3-ethyl-4-((4-((3-(2-oxopiperidin-1-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyrrolidine-3-carbonitrile,1-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(4-isopropylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(4-cyclobutylpiperazin-1-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-cyclopropyl-4-(4-ethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-methyl-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-ethyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-(4-ethyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-methyl-6-morpholinopyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,3-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,rac-(R)-3-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,rac-(R)-3-(3-((2-((2-cyclopropyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-ethyl-4-(4-methyl-2-oxopiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)morpholin-3-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one,4-(3-((2-((2-ethyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-cyclopropyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-chloro-2-((2-ethyl-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-chloro-2-((2-cyclopropyl-4-morpholinophenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-morpholinophenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((4-(4-ethylpiperazin-1-yl)-2-isopropylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-methyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-bromo-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,rac-4-(3-((2-((4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-(4-methyl-1,4-diazepan-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-chloro-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-bromo-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-cyclopropyl-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-5-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-bromo-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-chloro-2-((2-isopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-chloro-2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,rac-(R)-4-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one,4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one,1-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((4-methyl-6-morpholinopyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one,4-(3-((5-chloro-2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((4-ethyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((4-ethyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,(R)-4-(3-((2-((2-cyclopropyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,4-(3-((2-((2-cyclopropyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((2-cyclopropyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,4-(3-((2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,4-(3-((2-((2-(methoxymethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((4-ethyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile,3-(3-((2-((2-cyclopropyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,(S)-2-(4-(3-ethyl-4-((4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1-methylpiperazin-2-yl)acetonitrile,(R)-2-(4-(3-ethyl-4-((4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)-1-methylpiperazin-2-yl)acetonitrile,(S)-2-(1-methyl-4-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-2-yl)acetonitrile,(R)-2-(1-methyl-4-(3-methyl-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazin-2-yl)acetonitrile,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,4-(3-((2-((2-ethyl-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-((1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-(9-methyl-3,9-diazabicyclo[3.3.1]nonan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-(3-methyl-3,9-diazabicyclo[3.3.1]nonan-9-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-(1-methylpyrrolidin-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethynyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-(ethynyl-d)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-(ethyl-d5)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(2,2,2-trifluoroethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-(1,1-difluoroethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,5-(4-methylpiperazin-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzonitrile,2-methyl-2-(5-(4-methylpiperazin-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)propanenitrile,2-(5-(4-methylpiperazin-1-yl)-2-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)acetonitrile,4-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-(difluoromethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(3-((dimethylamino)methyl)azetidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one,3-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one,3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one,1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one,4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one,1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one,3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,(R)-3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,(S)-3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyltetrahydropyrimidin-2(1H)-one,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one,3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one,1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-4-methyl-1,4-diazepan-2-one,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1-methyl-1,4-diazepan-5-one,1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one,1-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-3-methyl-1,3-diazepan-2-one,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,(R)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,(S)-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-(piperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(piperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazinan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(2-oxo-1,3-oxazepan-3-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(4-methyl-2-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(4-methyl-7-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(4-methyl-7-oxo-1,4-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxo-1,3-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile,2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-4-((3-(3-methyl-2-oxo-1,3-diazepan-1-yl)propyl)amino)pyrimidine-5-carbonitrile,1-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one,4-(3-((2-((2-cyclopropyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,3-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one,3-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazepan-2-one,4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one,3-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one,4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-2,2-dimethyl-1,4-oxazepan-3-one,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one,8-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-5-oxa-8-azaspiro[2.6]nonan-9-one,4-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one,4-(3-((5-(difluoromethyl)-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one,4-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one,4-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(difluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,4-oxazepan-5-one,1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one,1-(3-((2-((2-ethyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one,1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one,1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one,1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one,1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one,1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one,1-(3-((2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one,1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azetidin-2-one,1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylazetidin-2-one,1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((5-(difluoromethyl)-2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((2-((2-ethyl-4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-3,3-dimethylpyrrolidin-2-one,1-(3-((2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((5-bromo-2-((2-ethyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((2-((4-(1,4-diazabicyclo[3.2.1]octan-4-yl)-2-ethylphenyl)amino)-5-bromopyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,1-(3-((5-bromo-2-((2-ethyl-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)pyrimidin-4-yl)amino)propyl)pyrrolidin-2-one,4-(3-((2-((4-(3-(diethylamino)propyl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-cyclopropyl-4-(3-morpholinopropyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,3-(3-((2-((2-ethyl-4-(2-(pyrrolidin-1-yl)ethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-cyclopropyl-4-((dimethylamino)methyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-methoxy-N-(1-methylpiperidin-4-yl)-4-((4-((3-(5-oxo-1,4-oxazepan-4-yl)propyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide,1-(3-((2-((2-cyclopropyl-4-(morpholinomethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,1-(3-((2-((2-ethyl-4-(2-(pyrrolidin-1-yl)propan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,4-(3-((2-((2-ethyl-4-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((4-(4-((dimethylamino)methyl)piperidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,44-(3-((2-((4-(3,3-dimethylpiperazin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-4-(3,3,5,5-tetramethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-cyclopropyl-4-(3,4,5-trimethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-ethyl-4-(3,3,4-trimethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-ethyl-4-(3,3,4,5,5-pentamethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,1-(3-((2-((2-chloro-4-(3,4-dimethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)azepan-2-one,3-(3-((2-((4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazepan-2-one,4-(3-((2-((4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((4-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one,3-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazepan-2-one,4-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((2-bromo-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazepan-2-one,4-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((6-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,1-(3-((2-((4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)azepan-2-one,4-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-methyl-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((4-(43-(3-((2-((2-ethyl-4-(4-methylpiperazine-1-carbonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,1-(3-((2-((2-cyclopropyl-4-(morpholinomethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)piperidin-2-one,3-(3-((2-((2-ethyl-4-(2-(pyrrolidin-1-yl)ethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-fluoro-4-(3-morpholinopropyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((4-(3-(diethylamino)propyl)-2-(trifluoromethyl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,3-oxazinan-2-one,4-(3-((2-((2-chloro-4-(3,4-dimethylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyridin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-methyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-chloro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-(14-(3-((2-((2-methyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-chloro-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-(1-hydroxyethyl)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-chloro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-(13-(3-((2-((2-methyl-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-chloro-4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-methyl-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-chloro-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,3-(3-((2-((2-(1-hydroxyethyl)-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,3-oxazinan-2-one,4-(3-((2-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-chloro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-methyl-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((2-chloro-4-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-3-one,4-(3-((2-((4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((2-(difluoromethoxy)-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,3-(3-((2-((2-cyclopropyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-6,6-dimethyl-1,3-oxazinan-2-one,4-(3-((2-((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,1-(3-((2-((2-cyclopropyl-4-(3-((dimethylamino)methyl)azetidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)piperidin-2-one,4-(3-((2-((4-(3-((dimethylamino)methyl)azetidin-1-yl)-2-ethylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,4-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)propyl)-1,4-oxazepan-5-one,and pharmaceutically acceptable salts, enantiomers, stereoisomers, andtautomers thereof.
 20. A pharmaceutical composition comprising acompound of claim 1 and a pharmaceutically acceptable excipient.
 21. Apharmaceutical composition comprising a compound of claim 1, one or moreadditional therapeutic agents, and a pharmaceutically acceptableexcipient.
 22. The pharmaceutical composition of claim 21, wherein theadditional therapeutic agent is a MAPKAP pathway inhibitor.
 23. Thepharmaceutical composition of claim 22, wherein the MAPKAP pathwayinhibitor is selected from the group consisting of a MEK inhibitor, anERK inhibitor, a RAF inhibitor, and a Ras inhibitor.
 24. Thepharmaceutical composition of claim 23, wherein the MEK inhibitor isselected from the group consisting of trametinib, selumetinib,cobimetinib, binimetinib, and pharmaceutically acceptable salts thereof,the ERK inhibitor is selected from the group consisting of ulixertinib,SCH772984, LY3214996, ravoxertinib, VX-11e, and pharmaceuticallyacceptable salts thereof, the RAF inhibitor is selected from the groupconsisting of LY3009120, LXH254, RAF709, dabrafenib, vemurafenib, andpharmaceutically acceptable salts thereof; or the Ras inhibitor isselected from the group consisting of AMG-510, MRTX849, andpharmaceutically acceptable salts thereof.
 25. The pharmaceuticalcomposition of claim 21, wherein the additional therapeutic agent is achemotherapeutic agent.
 26. A method of treating a cancer in a patientin need thereof, comprising administering to the patient atherapeutically effective amount of a compound of claim
 1. 27. Themethod of claim 26, wherein the cancer is selected from the groupconsisting of gastrointestinal stromal tumors, esophageal cancer,gastric cancer, melanomas, gliomas, glioblastomas, ovarian cancer,bladder cancer, pancreatic cancer, prostate cancer, lung cancers, breastcancers, renal cancers, hepatic cancers, osteosarcomas, multiplemyelomas, cervical carcinomas, cancers that are metastatic to bone,papillary thyroid carcinoma, non-small cell lung cancer, and colorectalcancers.
 28. The method of claim 26, further comprising administering tothe patient one or more additional therapeutic agents.
 29. The method ofclaim 28, wherein the additional therapeutic agent is a MAPKAP pathwayinhibitor.
 30. The method of claim 29, wherein the MAPKAP pathwayinhibitor is selected from the group consisting of a MEK inhibitor, anERK inhibitor, a RAF inhibitor, and a Ras inhibitor.
 31. The method ofclaim 30, wherein the MEK inhibitor is selected from the groupconsisting of trametinib, selumetinib, cobimetinib, binimetinib, andpharmaceutically acceptable salts thereof, the ERK inhibitor is selectedfrom the group consisting of ulixertinib, SCH772984, LY3214996,ravoxertinib, VX-11e, and pharmaceutically acceptable salts thereof; theRAF inhibitor is selected from the group consisting of LY3009120,LXH254, RAF709, dabrafenib, vemurafenib, and pharmaceutically acceptablesalts thereof; or the Ras inhibitor is selected from the groupconsisting of AMG-510, MRTX849, and pharmaceutically acceptable saltsthereof.
 32. The method of claim 28, wherein the additional therapeuticagent is a chemotherapeutic agent.
 33. The method of claim 32, whereinthe chemotherapeutic agent is a selected from the group consisting ofanti-tubulin agents, vinorelbine, DNA-alkylating agents, DNAintercalating agents, 5-fluorouracil, capecitabine, cytarabine,decitabine, 5-aza cytadine, gemcitabine, and methotrexate.
 34. Thecompound of claim 1, wherein the compound is selected from the groupconsisting of:

and pharmaceutically acceptable salts thereof.
 35. A compoundrepresented by:

or a pharmaceutically acceptable salt thereof.
 36. A compoundrepresented by:

or a pharmaceutically acceptable salt thereof.
 37. A compoundrepresented by:

or a pharmaceutically acceptable salt thereof.